Antiproliferative compounds and uses thereof

Abstract

The present invention provides a compound of formula I' or a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof, and a method of using the same for treating a cell proliferative disorder (eg, cancer)

Description

Technical Field

[0001] The present invention relates to compounds and methods useful for treating cell proliferative disorders (eg, cancer). The present invention also provides pharmaceutically acceptable compositions comprising the compounds of the present invention, and methods of using the compositions to treat various proliferative disorders. Background Art

[0002] Cell proliferative disorders include malignant and non-malignant cell populations that are morphologically and / or genotypically different from surrounding tissues. Examples of cell proliferative disorders include, for example, solid tumors, cancer, diabetic retinopathy, intraocular neovascular syndrome, macular degeneration, rheumatoid arthritis, psoriasis, and endometriosis. Cancer is a group of diseases involving abnormal cell proliferation that may 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 U.S. Therefore, it is desirable to provide patients with more options for other treatments for cell proliferative disorders. Summary of the Invention

[0003] It has now been found that the compounds of the present invention, and pharmaceutically acceptable compositions thereof, can be used to treat proliferative disorders (e.g., cancer). In one aspect, the present invention provides a compound of formula I:

[0004]

[0005] or a pharmaceutically acceptable salt thereof, wherein each variable is as defined and described herein.

[0006] The compounds of the present invention, and pharmaceutically acceptable compositions thereof, are useful in treating a variety of proliferative disorders (eg, cancer) as described herein. DETAILED DESCRIPTION

[0007] 1. General Description of Certain Embodiments of the Invention:

[0008] It has been found that the compounds of the present invention or salts thereof show significant efficacy in a variety of cell line-derived and patient-derived xenograft models. For example, it has been found that the compounds of the present invention or salts thereof cause complete and lasting regression in models of non-small cell lung cancer (NSCLC), myeloma, hepatocellular carcinoma (HCC), breast cancer, and melanoma. It has also been found that the compounds of the present invention cause enhanced cell viability inhibition, particularly cells in which Wolframin (WFS1) is overexpressed. Without wishing to be bound by any particular theory, it is believed that the compounds of the present invention act via a putative Ca2+-binding domain called Wolframin (WFS1). 2+The channel causes calcium release from the endoplasmic reticulum (ER), which induces ER stress and the "unfolded protein response" (UPR) and leads to cell death.

[0009] In one aspect, the present invention provides a compound of formula I:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, wherein:

[0012] Ring A is a ring selected from the group consisting of phenyl, 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;

[0013] Each R 1 are independently hydrogen or C 1-3 aliphatic; or

[0014] Two R's 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring;

[0015] Each R 2 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

[0016] Two R's 2 The groups are optionally taken together to form =0;

[0017] Each R 3 are independently hydrogen or C 1-3 an aliphatic group; or:

[0018] Two R's 3 The groups are optionally taken together to form =0;

[0019] Two R's 3 The groups are optionally taken together to form =CH2;

[0020] Two R's 3 The 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

[0021] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0022] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 7-10 membered saturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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:

[0023] Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1-2 oxo groups;

[0024] 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-;

[0025] m is 0, 1, or 2;

[0026] n is 0, 1, 2, 3, 4, or 5; and

[0027] p is 0, 1, or 2.

[0028] In one aspect, the present invention provides a compound of formula I':

[0029]

[0030] or a pharmaceutically acceptable salt thereof, wherein:

[0031] Ring A is a ring selected from the group consisting of phenyl, 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;

[0032] Each R1 is independently hydrogen or C optionally substituted by 1-6 halogens 1-3 an aliphatic group; or

[0033] Two R's 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring;

[0034] Each R 2 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

[0035] Two R's 2 The groups are optionally taken together to form =0; or

[0036] Two R's 2 The groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0037] Each R 3 are independently hydrogen, -OH or C 1-3 an aliphatic group; or

[0038] Two R's 3 The groups are optionally taken together to form =0; or

[0039] Two R's 3 The groups are optionally taken together to form =CH2; or

[0040] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0041] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0042] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 7-10 membered saturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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:

[0043] Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1-2 oxo groups;

[0044] Is a single bond or a double bond;

[0045] 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-;

[0046] m is 0, 1, or 2;

[0047] n is 0, 1, 2, 3, 4, or 5; and

[0048] p is 0, 1, or 2.

[0049] 2. Compounds and Definitions:

[0050] The compounds of the present invention include those generally described herein and are further illustrated by the classes, subclasses, and species disclosed herein. As used herein, the following definitions apply unless otherwise indicated. For the purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th edition. Additionally, the general principles of organic chemistry are described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th edition, Smith, MB and March, J. eds., John Wiley & Sons, New York: 2001, the entire contents of which are hereby incorporated by reference.

[0051] As used herein, the term "aliphatic" or "aliphatic group" means a linear (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is fully saturated or contains one or more unsaturated units, or a monocyclic or bicyclic hydrocarbon (also referred to herein as "carbocycle," "cycloaliphatic," or "cycloalkyl") that is fully saturated or contains one or more unsaturated units (but which is not an aromatic group), having a single point of attachment to the rest of the molecule. Unless otherwise indicated, an aliphatic group contains 1-6 aliphatic carbon atoms. In certain embodiments, an aliphatic group contains 1-5 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-4 aliphatic carbon atoms. In other embodiments, an aliphatic group contains 1-3 aliphatic carbon atoms, and in other embodiments, an aliphatic group contains 1-2 aliphatic carbon atoms. In certain embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6 hydrocarbon that is fully saturated or contains one or more units of unsaturation (but which is not an aromatic group), and has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl, and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl, or (cycloalkyl)alkenyl.

[0052] As used herein, the term "bicycle" or "bicyclic system" refers to any bicyclic system, i.e., carbocyclic or heterocyclic, saturated or with one or more unsaturated units, with one or more common atoms between the two rings of the ring system. Therefore, the term includes any allowed ring fusions, such as ortho-fusions or spirocycles. As used herein, the term "heterobicycle" is a subset of "bicyclic", which requires that one or more heteroatoms are present in one or both rings of the bicyclic. Such heteroatoms can be present in the ring connection portion and are optionally substituted, and can be selected from nitrogen (including N-oxides), oxygen, sulfur (including oxidized forms such as sulfones and sulfonates), phosphorus (including oxidized forms such as phosphates), boron, etc. In certain embodiments, the bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. As used herein, the term "bridged bicyclic" refers to any bicyclic system, i.e., carbocyclic or heterocyclic, saturated or partially unsaturated, with at least one bridge. As defined by IUPAC, "bridge" is an unbranched chain of atoms or atoms or valence bonds connecting two bridgeheads, wherein "bridgehead" is any backbone atom of a ring system, which is bonded to three or more backbone atoms (excluding hydrogen). In certain embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen or sulphur. Such bridged bicyclic groups are well known in the art, and include those groups set forth below, wherein each group is attached to the remainder of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise noted, a bridged bicyclic group is optionally substituted by one or more substituents set forth about an aliphatic group. Additional or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted. Exemplary bicyclics include:

[0053]

[0054] Exemplary bridged bicyclic rings include:

[0055]

[0056] The term "lower alkyl" refers to a C 1-4 Straight or branched chain alkyl groups. Exemplary lower alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tert-butyl.

[0057] The term "lower haloalkyl" refers to a C 1-4 Straight-chain or branched-chain alkyl.

[0058] The term "heteroatom" refers to one or more of oxygen, sulfur, nitrogen, phosphorus, or silicon (including any oxidized form of nitrogen, sulfur, phosphorus, or silicon; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, such as N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

[0059] As used herein, the term "unsaturated" refers to a moiety having one or more units of unsaturation.

[0060] The term "divalent C 1-8 (or C 1-6 ) saturated or unsaturated, straight or branched hydrocarbon chain” means a straight or branched divalent alkylene, alkenylene and alkynylene chain as defined herein.

[0061] The term "alkylene" refers to a divalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2) n -, wherein n is a positive integer, preferably 1-6, 1-4, 1-3, 1-2, or 2-3. A substituted alkylene chain is a polymethylene chain in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include the substituents described below for substituted aliphatic groups.

[0062] The term "alkenylene" refers to a divalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for substituted aliphatic groups.

[0063] As used herein, the term "cyclopropylenyl" refers to a divalent cyclopropyl radical of the following structure:

[0064]

[0065] The term "halogen" means F, Cl, Br or I.

[0066] The term "aryl" used alone or as part of a larger moiety (as in "aralkyl", "aralkoxy" or "aryloxyalkyl") refers to a monocyclic or bicyclic ring system having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic, and wherein each ring in the system contains 3-7 ring members. The term "aryl" is used interchangeably with the term "aryl ring". In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, which includes, but is not limited to, phenyl, biphenyl, naphthyl, anthracenyl, and the like, which may carry one or more substituents. The scope of the term "aryl" as used herein also includes groups in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimide, naphthylimide, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0067] The terms "heteroaryl" and "heteroar-" used alone or as part of a larger moiety (e.g., "heteroaralkyl" or "heteroaralkoxy") refer to groups having 5-10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 pi electrons shared in the cyclic array; and having one to five heteroatoms in addition to carbon atoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, as well as any quaternized form of a basic nitrogen. Heteroaryl groups include, but are not limited to, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, Azolyl, iso Azolyl, The term "heteroaryl" and "heteroaromatic-" as used herein also include groups wherein a heteroaromatic ring is fused to one or more aryl, cycloaliphatic or heterocyclyl rings, wherein the residue or point of attachment is on the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phen ... oxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl and pyrido[2,3-b]-1,4- Oxazine-3 (4H) -one. The heteroaryl group can be monocyclic or bicyclic. The term "heteroaryl" can be used interchangeably with the terms "heteroaryl ring," "heteroaryl group," or "heteroaromatic," any of which includes optionally substituted rings. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group, wherein the alkyl and heteroaryl portions are independently optionally substituted.

[0068] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic residue" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety which is saturated or partially unsaturated and has one or more, preferably one to four, heteroatoms as defined above in addition to carbon atoms. The term "nitrogen" when used with respect to a ring atom of a heterocycle includes substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or + NR (as in N-substituted pyrrolidinyl).

[0069] The heterocyclic ring may be attached to its side group at any heteroatom or carbon atom that results in a stable structure, and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic residues include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, Oxazolidinyl, piperazinyl, di The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety" and "heterocyclic residue" are used interchangeably herein and also include groups wherein the heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl or tetrahydroquinolinyl. The heterocyclyl group can be monocyclic or bicyclic. The term "heterocyclylalkyl" represents an alkyl substituted with a heterocyclyl, wherein the alkyl and heterocyclyl moieties are independently and optionally substituted.

[0070] 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.

[0071] As described herein, the compounds of the present invention may contain "optionally substituted" moieties. In general, the term "substituted", whether or not preceded by the term "optionally", means that one or more hydrogens of the designated moiety are replaced by a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted by more than one substituent selected from a specified set, the substituents at each position may be the same or different. The substituent combinations envisioned by the present invention are preferably those that are capable of forming stable or chemically feasible compounds. The term "stable" as used herein refers to a compound that does not undergo substantial change when subjected to conditions that allow it to be produced, detected, and in certain embodiments, recovered, purified, and used for one or more purposes disclosed herein.

[0072] Each optional substituent on a substitutable carbon is independently a monovalent substituent selected from the group consisting of: halogen; -(CH2); 0- 4R o ; -(CH2) 0-4 OR o ;-O(CH2) 0-4 R o ,-O-(CH2)0-4 C(O)OR o ; -(CH2) 0-4 CH(OR o )2;-(CH2) 0-4 SR o ; -(CH2) 0-4 Ph, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 Ph, which can be R o Substituted; -CH=CHPh, which can be R o Substitution; -(CH2) 0-4 O(CH2) 0-1 -pyridyl, which may be replaced by R o Substitution; -NO2; -CN; -N3; ​​-(CH2) 0-4 N(R o )2;-(CH2) 0- 4N(R o )C(O)R o ;-N(R o )C(S)R o ; -(CH2) 0-4 N(R o )C(O)NR o 2;-N(R o )C(S)NR o 2; -(CH2) 0-4 N(R o )C(O)OR o ;-N(R o )N(R o )C(O)R o ;-N(R o )N(R o )C(O)NR o 2;-N(R o )N(R o )C(O)OR o ; -(CH2) 0-4 C(O)R o ;-C(S)R o ; -(CH2) 0-4 C(O)OR o ; -(CH2) 0-4 C(O)SR o ; -(CH2) 0-4 C(O)OSiR o 3; -(CH2) 0-4 OC(O)R o ;-OC(O)(CH2)0-4 SR-、SC(S)SR o ; -(CH2) 0-4 SC(O)R o ; -(CH2) 0-4 C(O)NR o 2;-C(S)NR o 2;-C(S)SR o ;-SC(S)SR o , -(CH2) 0-4 OC(O)NR o 2;-C(O)N(OR o )R o ;-C(O)C(O)R o ;-C(O)CH2C(O)R o ;-C(NOR o )R o ; -(CH2) 0-4 SSR o ; -(CH2) 0-4 S(O)2R o ; -(CH2) 0-4 S(O)2OR o ; -(CH2) 0-4 OS(O)2R o ;-S(O)2NR o 2;-S(O)(NR o )R o ;-S(O)2N=C(NR o 2)2;-(CH2) 0-4 S(O)R o ;-N(R o )S(O)2NR o 2;-N(R o )S(O)2R o ;-N(OR o )R o ;-C(NH)NR o 2;-P(O)2R o ;-P(O)R o 2;-OP(O)R o 2;-OP(O)(OR o )2;SiR o 3;-(C 1-4 linear or branched alkylene)ON(R o )2; or -(C 1-4 linear or branched alkylene) C(O)ON(R o )2.

[0073] Each Ro are independently hydrogen, C 1-6 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, -CH2-(5-6 membered heteroaryl ring), or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or, notwithstanding the above definitions, two independent occurrences of R o Together with their intervening atoms, they form a 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, which may be in R o The saturated carbon atom is substituted by a divalent substituent selected from =O and =S; or each R o Optionally substituted with monovalent substituents independently selected from halogen, -(CH2) 0-2 R · 、-(halogenated R · ), -(CH2) 0-2 OH, -(CH2) 0-2 OR · 、-(CH2) 0-2 CH(OR · )2;-O(halogenated R · )、-CN、-N3、-(CH2) 0-2 C(O)R · 、-(CH2) 0-2 C(O)OH, -(CH2) 0-2 C(O)OR · 、-(CH2) 0-2 SR · 、-(CH2) 0-2 SH, -(CH2) 0-2 NH2, -(CH2) 0-2 NHR · 、-(CH2) 0-2 NR · 2. -NO2, -SiR · 3. -OSiR · 3. -C(O)SR · 、-(C 1-4 linear or branched alkylene)C(O)OR · or -SSR · .

[0074] Each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, if preceded by halogen, substituted only with one or more halogens; or wherein the optional substituents on the saturated carbon are divalent substituents independently selected from the group consisting of: =O, =S, =NNR * 2, =NNHC(O)R * , =NNHC(O)OR * , =NNHS(O)2R * , =NR * , =NOR * ,-O(C(R * 2)) 2-3 O-or-S(C(R * 2)) 2-3 S-, or a divalent substituent attached to a vicinal substitutable carbon of an "optionally substituted" group is -O(CR * 2) 2-3 O-, where each independent occurrence of R * Selected from hydrogen, C 1-6 Aliphatic or unsubstituted 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0075] When R * It is C 1-6 When the group is aliphatic, R * Optionally halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, if preceded by halogen, substituted only by one or more halogens.

[0076] The optional substituents on the substitutable nitrogen are independently Each of these are independently hydrogen, C 1-6 aliphatic, unsubstituted -OPh, or unsubstituted 5-6 membered saturated, partially unsaturated or aromatic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, or two independent occurrences of Together with their intervening atoms, they form an unsubstituted 3-12 membered saturated, partially unsaturated or aromatic monocyclic or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur; wherein when It is C 1-6 When the aliphatic group Optionally halogen, -R · 、-(halogenated R · ), -OH, -OR · 、-O(halogenated R · )、-CN、-C(O)OH、-C(O)OR · 、-NH2、-NHR · 、-NR · 2 or -NO2, where each R · Independently selected from C 1-4 Aliphatic, -CH2Ph, -O(CH2) 0-1 Ph, or a 5-6 membered saturated, partially unsaturated or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur, and wherein each R · is unsubstituted or, if preceded by halogen, substituted only by one or more halogens.

[0077] The term "pharmaceutically acceptable salt" as used herein refers to a salt that is suitable for use in contact with the tissues of humans and lower animals, without undue toxicity, irritation, allergic response, etc., and commensurate with a reasonable benefit / risk ratio, within the scope of reasonable medical judgment. 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 the present invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts formed of an amino group with an inorganic acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or an organic acid such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art (such as ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like.

[0078] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N + (C 1-4 Representative alkali metal or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include non-toxic ammonium, quaternary ammonium, and amine cations formed, where appropriate, using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates, and aryl sulfonates.

[0079] Unless otherwise stated, structures depicted herein are also intended to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the present compounds are within the scope of the invention. In addition, unless otherwise stated, structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, structures having a structure that includes the replacement of hydrogen by deuterium or tritium, or by 13 C- or 14 Compounds of the present structures in which a C-enriched carbon replaces a carbon are within the scope of the present invention. According to the present invention, such compounds can be used, for example, as analytical tools, probes in biological assays, or therapeutic agents.

[0080] 3. Description of exemplary embodiments:

[0081] In one aspect, the present invention provides a compound of formula I:

[0082]

[0083] or a pharmaceutically acceptable salt thereof, wherein:

[0084] Ring A is a ring selected from the group consisting of phenyl, 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;

[0085] Each R 1 are independently hydrogen or C 1-3 an aliphatic group; or

[0086] Two R's 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring;

[0087] Each R 2 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

[0088] Two R's2 The groups are optionally taken together to form =0;

[0089] Each R 3 are independently hydrogen or C 1-3 an aliphatic group; or:

[0090] Two R's 3 The groups are optionally taken together to form =0;

[0091] Two R's 3 The groups are optionally taken together to form =CH2;

[0092] Two R's 3 The 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

[0093] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0094] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 7-10 membered saturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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:

[0095] Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1-2 oxo groups;

[0096] 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-;

[0097] m is 0, 1, or 2;

[0098] n is 0, 1, 2, 3, 4, or 5; and

[0099] p is 0, 1, or 2.

[0100] In one aspect, the present invention provides a compound of formula I'

[0101]

[0102] or a pharmaceutically acceptable salt thereof, wherein:

[0103] Ring A is a ring selected from the group consisting of phenyl, 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;

[0104] Each R 1 is independently hydrogen or C optionally substituted by 1-6 halogens 1-3 an aliphatic group; or

[0105] Two R's 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring;

[0106] Each R 2 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

[0107] Two R's 2 The groups are optionally taken together to form =0; or

[0108] Two R's 2 The groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0109] Each R 3 are independently hydrogen, -OH or C 1-3 an aliphatic group; or

[0110] Two R's 3 The groups are optionally taken together to form =0; or

[0111] Two R's 3 The groups are optionally taken together to form =CH2; or

[0112] Two R's 3The groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or

[0113] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur;

[0114] Each R is independently hydrogen or an optionally substituted group selected from the group consisting of: C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 7-10 membered saturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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:

[0115] Two R groups on the same nitrogen optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1-2 oxo groups;

[0116] Is a single bond or a double bond;

[0117] 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-;

[0118] m is 0, 1, or 2;

[0119] n is 0, 1, 2, 3, 4, or 5; and

[0120] p is 0, 1, or 2.

[0121] As generally defined above, Is a single bond or a double bond.

[0122] In certain embodiments, is a single bond. In certain embodiments, It's a double bond.

[0123] In certain embodiments, Select from those depicted in Tables 1, 2, and 2A below.

[0124] As generally defined above, Ring A is a ring selected from phenyl, 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.

[0125] In certain embodiments, Ring A is phenyl. In certain 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.

[0126] In certain embodiments, Ring A is a 5-7 membered saturated or partially unsaturated carbocyclic ring. In certain embodiments, Ring A is an 8-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Ring A is a 5-6 membered heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. In certain embodiments, Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0127] In certain embodiments, Ring A is phenyl or wherein 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 certain embodiments, Ring B is selected from: In certain embodiments, Ring B is or

[0128] In certain embodiments, Ring A is selected from:

[0129]

[0130] In certain embodiments, Ring A is

[0131] In certain embodiments, Ring A is

[0132] In certain embodiments, Ring A is selected from:

[0133]

[0134] In certain embodiments, Ring A is

[0135] In certain embodiments, Ring A is selected from:

[0136]

[0137] In certain embodiments, Ring A is

[0138] In certain embodiments, Ring A is selected from:

[0139]

[0140] In certain embodiments, Ring A is

[0141] In certain embodiments, Ring A is selected from:

[0142]

[0143] In certain embodiments, Ring A is selected from:

[0144]

[0145] In certain embodiments, Ring A is selected from:

[0146]

[0147] In certain embodiments, Ring A is selected from:

[0148]

[0149] In certain embodiments, Ring A is selected from:

[0150]

[0151] In certain embodiments, Ring A is

[0152] In certain embodiments, Ring A is One R 2 is -OH, and yes It may also exist in tautomeric forms:

[0153] In certain embodiments, Ring A is selected from those depicted in Tables 1 and 2 below.

[0154] In certain embodiments, Ring A is selected from those depicted in Table 2A below.

[0155] As defined generally above, each R 1 are independently hydrogen or C 1-3 aliphatic group; or two R 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring.

[0156] In certain embodiments, R 1 is hydrogen. In certain embodiments, R 1 It is C 1-3 In certain embodiments, two R 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring.

[0157] In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 In certain embodiments, R 1 It is isopropyl.

[0158] In certain embodiments, R 1 Attached to position 5 of the pyrimidine. In certain embodiments, R 1 Attached to position 6 of the pyrimidine.

[0159] In certain embodiments, both R 1 The groups are optionally taken together with their intervening atoms to form a 5-8 membered partially unsaturated fused carbocyclic ring. 1 The groups are optionally taken together with their intervening atoms to form a 5-membered partially unsaturated fused carbocyclic ring. 1 The groups are optionally taken together with their intervening atoms to form a 6-membered partially unsaturated fused carbocyclic ring. 1 The groups are optionally taken together with their intervening atoms to form a 7-membered partially unsaturated fused carbocyclic ring. 1 The groups are optionally taken together with their intervening atoms to form an 8-membered partially unsaturated fused carbocyclic ring.

[0160] In certain embodiments, R 1 is C optionally substituted 1-6 times by halogen 1-3 In certain embodiments, R 1 is C optionally substituted 1-6 times by halogen 1-3 In certain embodiments, R 1 is C optionally substituted 1-6 times by fluorine 1-3In certain embodiments, R 1 is C optionally substituted 1-3 times by fluorine 1-3 In certain embodiments, R 1 Yes -CF3.

[0161] In certain embodiments, R 1 Select from those depicted in Tables 1 and 2 below.

[0162] In certain embodiments, R 1 Select from those depicted in Table 2A below.

[0163] As defined generally above, each R 2 are independently hydrogen, halogen (F, Cl, Br or I), -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 R 2 The groups are optionally taken together to form =0.

[0164] In certain embodiments, R 2 is hydrogen. In certain embodiments, each R 2 are 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 R 2 The groups are optionally taken together to form =0.

[0165] In certain embodiments, R 2 In certain embodiments, R 2 Is Cl. In certain embodiments, R 2 In certain embodiments, R 2 In certain embodiments, R 2 is -C(O)OR. In certain embodiments, R 2 is -C(O)NR2. In certain embodiments, R 2 In certain embodiments, R 2 is -NRC(O)R. In certain embodiments, R 2 is -NRC(O)OR. In certain embodiments, R 2 is -NRS(O)2R. In certain embodiments, R 2is independently -OR. In certain embodiments, R 2 is -P(O)R2. In certain embodiments, R 2 In certain embodiments, R 2 is -S(O)R. In certain embodiments, R 2 is -S(O)2R. In certain embodiments, R 2 is -S(O)(NH)R. In certain embodiments, R 2 is R. In certain embodiments, two R 2 The groups are optionally taken together to form =0.

[0166] In certain embodiments, R 2 is -S(O)2NR2. In certain embodiments, R 2 It is -S(O)2NH2.

[0167] In certain embodiments, R 2 It is C 1-6 In certain embodiments, R 2 is a 3-8 membered saturated monocyclic carbocyclic ring. 2 is a 7-10 membered saturated spiro bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 2 is a 7-10 membered saturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 2 is a 4-8 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 2 is a 5-6 membered monocyclic heteroaromatic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0168] In certain embodiments, each R 2 Independently selected from:

[0169] Halogen (e.g., Cl), -NH2, -CH3, -CF3, -CH2CH3, =O,-OH,-COOH,

[0170]

[0171] In certain embodiments, R 2Selected from -S(O)2NH2, -OCHF2, -OCF3, -C≡CH, -O-CH2-C≡CH,

[0172] In certain embodiments, R 2 It is C 1-6 aliphatic, which is optionally substituted 1-4 times by halogen, -OH, NH2, -OCH3, -NHC(O)CH3, -S(O)2CH3 or -N(CH3)C(O)CH3. 2 Selected from CH3, -CF3, -CH2CH3,

[0173] In certain embodiments, R 2 It is C 1-6 aliphatic, which is 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. 2 yes

[0174] In certain embodiments, R 2 It is C 1-6 aliphatic group, which is optionally replaced by -S(O)2-(CH2) 0-6 Group substitution, where (CH2) 0-6 is optionally substituted 1-4 times with halogen, -OH, NH2 or -OCH3. In certain embodiments, R 2 It is C 1-6 aliphatic group, which is optionally replaced by -S(O)2-(CH2) 0-6 Group substitution, where (CH2) 0-6 is unsubstituted. In certain embodiments, R 2 It is C 1-6 aliphatic, which is optionally substituted with -S(O)2-CH3 or -S(O)2-CH2-CH3. 2 It is C 1-6 aliphatic, which is optionally substituted with -S(O)2-CH3. In certain embodiments, R 2 is -CH2-S(O)2-CH3. In certain embodiments, R 2 is -CH2-S(O)2-CH2-CH3. In certain embodiments, R 2is -CH2-CH2-S(O)2-CH3. In certain embodiments, R 2 is -CH2-CH2-S(O)2-CH2-CH3. In certain embodiments, R 2 Selected from

[0175] In certain embodiments, R 2 is unsubstituted C 1-6 In certain embodiments, R 2 Yes -C≡CH.

[0176] In certain embodiments, R 2 is a 3-6 membered saturated monocyclic carbocyclic ring. 2 yes

[0177] In certain embodiments, R 2 is a 7-10 membered saturated spiro bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen. 2 Selected from

[0178] In certain embodiments, R 2 is a 7-10 membered saturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen. 2 yes

[0179] In certain embodiments, R 2 is a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted by halogen, -OH, -CH3, -OCH3, =O or In certain embodiments, R 2 Selected from

[0180] In certain embodiments, R 2 is a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted by halogen, -OH, -CH3, -OCH3, =O, In certain embodiments, R 2 Selected from

[0181] In certain embodiments, R 2is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 2 Selected from

[0182] In certain embodiments, R 2 is -C(O)OR, where R is hydrogen or C 1-6 In certain embodiments, R 2 is -C(O)OH. In certain embodiments, R 2 Yes -C(O)OC 1-6 aliphatic group, wherein the C 1-6 Aliphatic groups are unsubstituted. In certain embodiments, R 2 yes In certain embodiments, R 2 yes

[0183] In certain embodiments, R 2 is -C(O)NR2, wherein each R is independently hydrogen, C optionally substituted with -N(CH3)2 1-6 aliphatic, an unsubstituted 3-6 membered saturated monocyclic carbocyclic ring, or an unsubstituted 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen, or two R together with their intervening atoms form a 4-7 membered saturated and unsubstituted heteroaryl ring. In certain embodiments, R 2 Selected from

[0184] In certain embodiments, R 2 Is -C(O)NR2, wherein the two R together with their intervening atoms form a 4-7 membered saturated ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which are optionally substituted with 1-2 oxo groups. In certain embodiments, R 2 Is -C(O)NR2, wherein the two R together with their intervening atoms form a 4-7 membered saturated and unsubstituted ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur. In certain embodiments, R 2 yes

[0185] In certain embodiments, R 2 is -NR2, wherein each R is independently:

[0186] hydrogen;

[0187] C1-6 aliphatic group, which is optionally substituted with -OH, Replace 1-2 times;

[0188] unsubstituted 3-6 membered saturated monocyclic carbocycle;

[0189] a 4-6 membered saturated monocyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen or oxygen, which is optionally substituted 1-2 times with CH3, -OH, -C(O)OC(CH3)3 or -C(O)CH3; or

[0190] A 6-membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted 1-2 times with -CH3 or -NH2.

[0191] In certain embodiments, R 2 Selected from

[0192] In certain embodiments, R 2 is -NHC(O)R, wherein R is C optionally substituted 1-3 times by halogen, -OCH3, -N(CH3)2 or -OH 1-6 aliphatic, a 3-6 membered saturated monocyclic carbocyclic ring optionally substituted 1-2 times by halogen or -OH, or a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted 1-2 times by halogen, -OH or -CH3. 2 Selected from

[0193] In certain embodiments, R 2 is -NHC(O)R, wherein R is C optionally substituted 1-3 times by halogen, -OCH3, -N(CH3)2 or -OH 1-6 In certain embodiments, C 1-6 An aliphatic group is a straight (ie, unbranched) or branched, substituted or unsubstituted saturated hydrocarbon chain. In certain embodiments, C 1-6 Aliphatic groups are linear (ie, unbranched) or branched, substituted or unsubstituted hydrocarbon chains containing monocyclic hydrocarbons. In certain embodiments, C 1-6 The aliphatic group is selected from In certain embodiments, R 2 Selected from

[0194] In certain embodiments, R 2is -NHC(O)OR, wherein R is unsubstituted C 1-6 In certain embodiments, R 2 yes

[0195] In certain embodiments, R 2 is -NHS(O)2R, where R is unsubstituted C 1-6 In certain embodiments, R 2 yes

[0196] In certain embodiments, R 2 is -OR, wherein R is H; optionally substituted by halogen, -OH, Substituted C 1-6 or a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen. 2 Selected from -OH,

[0197] In certain embodiments, R 2 is -OR, wherein R is optionally substituted with halogen, -OH, -C(O)NHC 1-4 Aliphatic groups, -COOH, -C(O)OC 1-4 Aliphatic groups, -CN, -SO2C 1-4 aliphatic group or Substituted C 1-6 Aliphatic group.

[0198] In certain embodiments, R 2 Selected from

[0199] In certain embodiments, R 2 is -OR, where R is unsubstituted C 1-6 In certain embodiments, R 2 It is -O-CH2-C≡CH.

[0200] In certain embodiments, R 2 is -P(O)R2, wherein each R is independently unsubstituted C 1-6 In certain embodiments, R 2 yes

[0201] In certain embodiments, R 2 is -SR, where R is unsubstituted C 1-6Aliphatic group.

[0202] In certain embodiments, R 2 yes

[0203] In certain embodiments, R 2 is -S(O)R, where R is unsubstituted C 1-6 In certain embodiments, R 2 yes

[0204] In certain embodiments, R 2 is -S(O)2R, where R is unsubstituted C 1-6 aliphatic or 3-6 membered saturated monocyclic carbocyclic ring. 2 Selected from

[0205] In certain embodiments, R 2 is -S(O)(NH)R, wherein R is unsubstituted C 1-6 In certain embodiments, R 2 yes

[0206] In certain embodiments, R 2 In certain embodiments, R 2 Selected from -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 C 1-6 An aliphatic group wherein one or more methylene units are replaced by -C(O)-, -S(O)-, -S(O)2-, -P(O)-, or -P(O)2-. In certain embodiments, R 2 It is C 1-6 An aliphatic group wherein one or more methylene units are replaced by -C(O)-, -S(O)-, -S(O)2-, -P(O)-, or -P(O)2-. In certain embodiments, R 2 It is C 1-6 An aliphatic group wherein one or more methylene units are replaced by -S(O)2-. In certain embodiments, R 2 Selected from: In certain embodiments, R 2Selected from: In certain embodiments, R 2 Selected from: In certain embodiments, R 2 Selected from: In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes In certain embodiments, R 2 yes

[0207] In certain embodiments, both R 2 The groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 2 The groups optionally form a 3-8 membered saturated spirocyclic carbocyclic ring together with their intervening atoms. 2 The groups are optionally taken together with their intervening atoms to form a 3-membered saturated spirocyclic carbocyclic ring. 2 The groups are optionally taken together with their intervening atoms to form a 4-, 5-, or 6-membered saturated spirocyclic carbocycle.

[0208] In certain embodiments, both R 2 In certain embodiments, the two R 2 In certain embodiments, the two R 2 Each of the groups is independently an optionally substituted C 1-6 In certain embodiments, the two R 2 Each of the groups is independently unsubstituted C 1-6 In certain embodiments, the two R 2 Each of the groups is independently unsubstituted C 1-6 In certain embodiments, the two R 2 Each of the groups is a methyl group.

[0209] In certain embodiments, R 2 Select from those depicted in Tables 1 and 2 below.

[0210] In certain embodiments, R 2 Select from those depicted in Table 2A below.

[0211] As defined generally above, each R 3 are independently hydrogen or C 1-3 an aliphatic group; or:

[0212] Two R's 3 The groups are optionally taken together to form =0;

[0213] Two R's 3 The groups are optionally taken together to form =CH2;

[0214] Two R's 3 The 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

[0215] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0216] In certain embodiments, R 3 is hydrogen. In certain embodiments, R 3 It is C 1-3 an aliphatic group; or:

[0217] Two R's 3 The groups are optionally taken together to form =0;

[0218] Two R's 3 The groups are optionally taken together to form =CH2;

[0219] Two R's 3 The 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

[0220] Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0221] In certain embodiments, R 3 It is C 1-3 In certain embodiments, two R 3 The groups are optionally taken together to form =0. In certain embodiments, the two R 3 The groups are optionally taken together to form =CH2. In certain embodiments, the two R 3 The 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. 3The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

[0222] In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 In certain embodiments, R 3 It is isopropyl.

[0223] In certain embodiments, both R 3 The 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. 3 The groups optionally form, together with their intervening atoms, a 5-membered saturated spirocyclic ring having 0-2 oxygen atoms. 3 The groups optionally together with their intervening atoms form It forms a spiro ring at the carbon atom at position 2.

[0224] In certain embodiments, both R 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged bicyclic ring having 1-2 heteroatoms independently selected from nitrogen and oxygen. 3 The groups are optionally taken together with their intervening atoms to form a saturated bridged bicyclic ring having 1-2 nitrogen atoms, wherein the saturated bridged bicyclic ring comprises a 6-membered ring and a 7-membered ring. In certain embodiments, the two R 3 Group and Optionally forming

[0225] In certain embodiments, R 3 It is -OH.

[0226] In certain embodiments, both R 3 The groups are optionally taken together with their intervening atoms to form a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. 3 The 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. 3 The groups are optionally taken together with their intervening atoms to form a 3 or 4 membered saturated spirocyclic carbocyclic ring. 3 The groups are optionally taken together with their intervening atoms to form a 3-membered saturated spirocyclic carbocycle.

[0227] In certain embodiments, R 3 Select from those depicted in Tables 1 and 2 below.

[0228] In certain embodiments, R 3 Select from those depicted in Table 2A below.

[0229] As generally defined above, each R is independently hydrogen or an optionally substituted group selected from: C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 7-10 membered saturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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 optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1-2 oxo groups.

[0230] In certain embodiments, R is hydrogen. In certain embodiments, each R is independently an optionally substituted group selected from: C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocycle, phenyl, a 7-10 membered saturated spiro bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused bicyclic heterocycle having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 4-8 membered saturated or partially unsaturated monocyclic heterocycle 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 optionally form, together with their intervening atoms, a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, which is optionally substituted with 1-2 oxo groups.

[0231] In certain embodiments, R is optionally substituted C 1-6Aliphatic. In certain embodiments, R is an optionally substituted 3-8 yuan saturated or partially unsaturated monocyclic carbocyclic ring. In certain embodiments, R is an optionally substituted phenyl. In certain embodiments, R is an optionally substituted 7-10 yuan saturated spiro bicyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, R is an optionally substituted 7-10 yuan saturated or partially unsaturated fused bicyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, R is an optionally substituted 4-8 yuan saturated or partially unsaturated monocyclic heterocyclic ring with 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, R is an optionally substituted 5-6 yuan monocyclic heteroaromatic ring with 1-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In certain embodiments, 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, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen, and sulfur, optionally substituted with 1-2 oxo groups.

[0232] In certain embodiments, R is selected from those depicted in Tables 1 and 2 below.

[0233] In certain embodiments, R is selected from those depicted in Table 2A below.

[0234] As generally defined above, 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-.

[0235] In certain embodiments, X is -O-. In certain embodiments, X is -N(R)-. In certain embodiments, X is -N(S(O)2(R))-. In certain embodiments, X is S. In certain embodiments, X is -S(O)-. In certain embodiments, X is -S(O)2-. In certain embodiments, X is -CH2-. In certain embodiments, X is -CH(R 3 )-. In certain embodiments, X is -C(R 3 )2-.

[0236] In certain embodiments, X is -N(S(O)2(R))-, wherein R is C 1-6 In certain embodiments, X is -N(S(O)2CH3)-. In certain embodiments, X is -CH(R 3 )-, where R 3 It is C 1-6In certain embodiments, X is -CH(CH3)-. In certain embodiments, X is -C(R 3 )2-, where R 3 It is C 1-6 In certain embodiments, X is -C(CH3)2-.

[0237] In certain embodiments, X is selected from those depicted in Tables 1 and 2 below.

[0238] In certain embodiments, X is selected from those depicted in Table 2A below.

[0239] As generally defined above, m is 0, 1 or 2.

[0240] In certain embodiments, m is 0. In certain embodiments, m is 1. In certain embodiments, m is 2.

[0241] In certain embodiments, m is selected from those depicted in Tables 1 and 2 below.

[0242] In certain embodiments, m is selected from those depicted in Table 2A below.

[0243] As generally defined above, n is 0, 1, 2, 3, 4 or 5.

[0244] In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 5.

[0245] In certain embodiments, n is selected from those depicted in Tables 1 and 2 below.

[0246] In certain embodiments, n is selected from those depicted in Table 2A below.

[0247] As generally defined above, p is 0, 1 or 2.

[0248] In certain embodiments, p is 0. In certain embodiments, p is 1. In certain embodiments, p is 2.

[0249] In certain embodiments, p is selected from those depicted in Tables 1 and 2 below.

[0250] In certain embodiments, p is selected from those depicted in Table 2A below.

[0251] In certain embodiments, the present invention provides compounds of Formula Ia or Ib:

[0252]

[0253] or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 、R 2 、R 3 Each of R, X, m, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0254] In certain embodiments, the present invention provides compounds of Formula II:

[0255]

[0256] or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 、R 2 、R 3 Each of R, n and p, individually and or in combination, is as defined above and described in the embodiments herein.

[0257] In certain embodiments, the present invention provides compounds of Formula II-a or II-b:

[0258]

[0259] or a pharmaceutically acceptable salt thereof, wherein Ring A, R 1 、R 2 、R 3 Each of R, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0260] In certain embodiments, the present invention provides compounds of formula III

[0261]

[0262] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 Each of R, m, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0263] In certain embodiments, the present invention provides compounds of Formula III-a or III-b:

[0264]

[0265] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 Each of R, m, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0266] In certain embodiments, the present invention provides compounds of formula IV

[0267]

[0268] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 、R 2 、R 3 Each of R, m, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0269] In certain embodiments, the present invention provides compounds of Formula IV-a or IV-b:

[0270]

[0271] or a pharmaceutically acceptable salt thereof, wherein ring B, R 1 、R 2 、R 3 Each of R, m, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0272] In certain embodiments, the present invention provides compounds of formula V

[0273]

[0274] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 Each of R, X, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0275] In certain embodiments, the present invention provides compounds of Formula Va or Vb:

[0276]

[0277] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 3 Each of R, X, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0278] In certain embodiments, the present invention provides compounds of formula VI

[0279]

[0280] or a pharmaceutically acceptable salt thereof, wherein Ring B, R 1 、R 2 、R 3Each of R, X, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0281] In certain embodiments, the present invention provides compounds of Formula VI-a or VI-b:

[0282]

[0283] or a pharmaceutically acceptable salt thereof, wherein Ring B, R 1 、R 2 、R 3 Each of R, X, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0284] In certain embodiments, the present invention provides compounds of formula VII

[0285]

[0286] or a pharmaceutically acceptable salt thereof, wherein n' is 1 or 2, and R 2’ Is halogen or -OC 1-3 aliphatic group, and wherein R 1 、R 2 、R 3 Each of R, X, and p, individually and in combination, is as defined above and described in the embodiments herein. In certain embodiments, n' is 1. In certain embodiments, n' is 2. In certain embodiments, R 2’ is F. In certain embodiments, R 2’ Is Cl. In certain embodiments, R 2’ is Br. In certain embodiments, R 2’ is 1. In certain embodiments, R 2’ In certain embodiments, R 2’ In certain embodiments, R 2’ In certain embodiments, R 2’ It is -OCH(CH3)2.

[0287] In certain embodiments, n' is selected from those depicted in Tables 1, 2, and 2A below.

[0288] In certain embodiments, R 2’ Select from those depicted in Tables 1, 2, and 2A below.

[0289] In certain embodiments, the present invention provides compounds of Formula VII-a or VII-b:

[0290]

[0291] or a pharmaceutically acceptable salt thereof, wherein R 1 、R 2 、R 2’ 、R 3 Each of R, X, p and n', individually and or in combination, is as defined above and described in the embodiments herein.

[0292] In certain embodiments, the present invention provides compounds of Formula VIII:

[0293]

[0294] or a pharmaceutically acceptable salt thereof, wherein n" is 0, 1, 2, 3 or 4, and wherein Ring B, R 1 、R 2 、R 2’ 、R 3 Each of R, X, and p, individually and in combination, is as defined above and described in the embodiments herein.

[0295] In certain embodiments, n" is 0. In certain embodiments, n" is 1. In certain embodiments, n" is 2. In certain embodiments, n" is 3. In certain embodiments, n" is 4.

[0296] In certain embodiments, n" is selected from those depicted in Tables 1, 2, and 2A below.

[0297] In certain embodiments, the present invention provides compounds of Formula VIII-a or VIII-b:

[0298]

[0299] or a pharmaceutically acceptable salt thereof, wherein Ring B, R 1 、R 2 、R 2’ 、R 3 Each of ", R, X, p and n", individually and in combination, is as defined above and described in the embodiments herein.

[0300] In certain embodiments, the present invention provides compounds of Formula IX:

[0301]

[0302] or a pharmaceutically acceptable salt thereof, wherein R 2’ is a halogen, and R 2 Each of n', individually and in combination, is as defined above and described in the embodiments herein.

[0303] In certain embodiments, the present invention provides compounds of Formula IX-a or IX-b:

[0304]

[0305] or a pharmaceutically acceptable salt thereof, wherein R 2’ is a halogen, and R 2 Each of n', individually and in combination, is as defined above and described in the embodiments herein.

[0306] In certain embodiments, the present invention provides compounds of Formula X, XI, or XII:

[0307]

[0308] or a pharmaceutically acceptable salt thereof, wherein R 2’ is a halogen, and each R 2 As defined above and described in the embodiments herein, both individually and in combination.

[0309] In certain embodiments, the present invention provides a compound of Formula Xa, Xb, XI-a, XI-b, XII-a, or XII-b:

[0310]

[0311]

[0312] or a pharmaceutically acceptable salt thereof, wherein R 2’ is a halogen, and each R 2 As defined above and described in the embodiments herein, both individually and in combination.

[0313] In certain embodiments, the present invention provides compounds of Formula X, XI, XII, Xa, Xb, XI-a, XI-b, XII-a, or XII-b as shown above, wherein R 2’ is Cl and each R 2 Selected from: halogen (e.g., Cl), -NH2, -CH3, -CF3, -CH2CH3, =O,-OH,-COOH,

[0314] -OCF3,-C≡CH,-O-CH2-C≡CH,

[0315] In certain embodiments, exemplary compounds of the invention are shown in Tables 1 and 2 below.

[0316] In certain embodiments, exemplary compounds of the invention are shown below in Table 2A.

[0317] In certain embodiments, the present invention provides a compound selected from those listed in Table 1, or a pharmaceutically acceptable salt thereof.

[0318] In certain embodiments, the present invention provides a compound selected from those listed in Table 2, or a pharmaceutically acceptable salt thereof.

[0319] In certain embodiments, the present invention provides a compound selected from those listed in Table 2A, or a pharmaceutically acceptable salt thereof.

[0320] In certain embodiments, the present invention provides the trifluoroacetic acid salt of compound D-150.

[0321] Table 1: Exemplary compounds

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341] Compounds I-120 to I-123 are stereoisomers of the following formula: Compounds 1-120 to 1-123 can be separated by chiral purification (see, e.g., Example 18). Thus, in certain embodiments, the present invention provides a stereoisomer selected from compounds 1-120 to 1-123 or a pharmaceutically acceptable salt thereof.

[0342] Compounds I-164 to I-167 are stereoisomers of the following formula: Compounds 1-164 to 1-167 can be isolated by chiral purification (see, for example, Example 41). Thus, in certain embodiments, the present invention provides a stereoisomer selected from compounds 1-164 to 1-167 or a pharmaceutically acceptable salt thereof.

[0343] Compounds 1-209 and 1-210 are stereoisomers of the following formula: Compounds 1-209 and 1-210 can be separated by chiral purification (see, e.g., Example 52). Thus, in certain embodiments, the present invention provides a stereoisomer selected from compounds 1-209 to 1-210, or a pharmaceutically acceptable salt thereof.

[0344] Compounds I-211 and I-212 are stereoisomers of the following formula: Compounds 1-211 and 1-212 can be separated by chiral purification (see, e.g., Example 52). Thus, in certain embodiments, the present invention provides a stereoisomer selected from compounds 1-211 to 1-212 or a pharmaceutically acceptable salt thereof.

[0345] Table 2. Exemplary compounds

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357] Table 2A: Exemplary compounds

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372] 4. General methods for providing compounds of the present invention:

[0373] The compounds of the present invention can generally be prepared or isolated by synthetic and / or semisynthetic methods known to those skilled in the art for analogous compounds and by the methods described in detail in the Examples herein.

[0374] In the following schemes, where specific protecting groups ("PG"), leaving groups ("LG"), or transformation conditions are depicted, one of ordinary skill in the art will recognize that other protecting groups, leaving groups, and transformation conditions are also suitable and encompassed. Such groups and transformations are described in detail in March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, MB Smith and J. March, 5th edition, John Wiley & Sons, 2001, Comprehensive Organic Transformations, RC Larock, 2nd edition, John Wiley & Sons, 1999, and Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, the entire contents of each of which are hereby incorporated herein by reference.

[0375] As used herein, the phrase "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), diazo wait.

[0376] As used herein, the phrase "oxy protecting group" includes, for example, carbonyl protecting groups, hydroxy protecting groups, and the like. Hydroxy protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd edition, John Wiley & Sons, 1999, and Philip Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, which are incorporated herein by reference in their entirety. Examples of suitable hydroxy protecting groups include, but are not limited to, esters, allyl ethers, ethers, silyl ethers, alkyl ethers, aryl alkyl ethers, and alkoxyalkyl ethers. Examples of such esters include formates, acetates, carbonates, and sulfonates. Specific examples include: formates, benzoylformates, chloroacetates, trifluoroacetates, methoxyacetates, triphenylmethoxyacetates, p-chlorophenoxyacetates, 3-phenylpropionates, 4-oxopentanoate, 4,4-(ethylenedisulfide)pentanoate, pivaloate (pivaloyl), crotonates, 4-methoxy-crotonates, benzoates, p-benzylbenzoate, 2,4,6-trimethylbenzoate, carbonates such as methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, and p-nitrobenzyl carbonates. Examples of such silyl ethers include trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, and other trialkylsilyl ethers. Alkyl ethers include methyl, benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, trityl, tert-butyl, allyl, and allyloxycarbonyl ethers or derivatives. Alkoxyalkyl ethers include acetals such as methoxymethyl, methylthiomethyl, (2-methoxyethoxy)methyl, benzyloxymethyl, β-(trimethylsilyl)ethoxymethyl, and tetrahydropyranyl ether. Examples of aryl alkyl ethers include benzyl, p-methoxybenzyl (MPM), 3,4-dimethoxybenzyl, O-nitrobenzyl, p-nitrobenzyl, p-halobenzyl, 2,6-dichlorobenzyl, p-cyanobenzyl, and 2- and 4-picoline.

[0377] Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, TW Greene and PGM Wuts, 3rd Edition, John Wiley & Sons, 1999, and Philip Kocienski, "Protecting Groups", Georg Thieme Verlag Stuttgart, New York, 1994, which are incorporated herein by reference in their entireties. Suitable amino protecting groups include, but are not limited to, aralkylamines, carbamates, cyclic imides, allylamines, amides, and the like. Examples of such groups include tert-butyloxycarbonyl (BOC), ethyloxycarbonyl, methoxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxycarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, and the like.

[0378] It will be appreciated by those skilled in the art that the various functional groups present in the compound of the present invention such as aliphatic groups, alcohol, carboxylic acid, ester, amides, aldehyde, halogen and nitrile can be converted to each other by technology well known in the art, 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 ", the 5th edition, Smith, MB and March, J. compile, John Wiley & Sons, New York: 2001, which is incorporated herein by reference in its entirety. Such mutual conversion may require one or more of the aforementioned technologies, and some methods for synthesizing the compound of the present invention are described hereinafter.

[0379] In one aspect, the present invention provides a method for synthesizing a compound of formula I or its subformulae or a salt thereof, the method comprising: The compound or its salt of formula The compound or its salt, wherein ring A, R 1 、R 2 、R 3 Each of R, X, m, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0380] In certain embodiments, the present invention provides a A compound or a salt thereof, wherein R 1Each of R, R and m, individually and in combination, is as defined above and described in the embodiments herein.

[0381] In certain embodiments, the present invention provides a A compound or a salt thereof, wherein ring A, R 2 、R 3 Each of R, X, n and p, individually and in combination, is as defined above and described in the embodiments herein.

[0382] In one aspect, the present invention provides a method for synthesizing a compound of formula I' or a subformula thereof or a salt thereof, the method comprising: The compound or its salt of formula The compound or its salt, wherein ring A, R 1 、R 2 、R 3 、 Each of R, X, m, n and p, individually and in combination, are as defined above and described in the embodiments herein.

[0383] In certain embodiments, the present invention provides a A compound or a salt thereof, wherein ring A, R 2 、R 3 、 Each of R, X, n and p, individually and in combination, are as defined above and described in the embodiments herein.

[0384] In certain embodiments, the present invention provides a method for synthesizing a compound of formula VII or a salt thereof, the method comprising: The compound or its salt of formula The compound or its salt, wherein R 1 、R 2 、R 2’ 、R 3 Each of R, X, p and n', individually and in combination, is as defined above and described in the embodiments herein.

[0385] In certain embodiments, the present invention provides a method for synthesizing a compound of formula VIII or a salt thereof, the method comprising: The compound or its salt of formula The compound or its salt, wherein ring B, R 1 、R 2 、R 2’ 、R 3 Each of ", R, X, p and n", individually and in combination, is as defined above and described in the embodiments herein.

[0386] In certain embodiments, the present invention provides a A compound or a salt thereof, wherein R 1 Each of R, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19, R20, R21, R22, R23, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34

[0387] In certain embodiments, the present invention provides a A compound or a salt thereof, wherein each R 2 、R 2’ 、R 3 , R, X, p and n' are as defined above and described in the embodiments herein, individually and in combination.

[0388] In certain embodiments, the present invention provides a A compound or a salt thereof, wherein ring B, R 2 、R 2’ 、R 3 Each of ", R, X, p and n", individually and in combination, is as defined above and described in the embodiments herein.

[0389] 5. Use, preparation and administration:

[0390] Pharmaceutically acceptable compositions

[0391] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable derivative thereof and a pharmaceutically acceptable carrier, adjuvant or vehicle. In certain embodiments, the amount of the compound in the composition of the present invention is the amount that effectively causes the death of cancer cells in a biological sample or a patient. In certain embodiments, the amount of the compound in the composition of the present invention is the amount that effectively induces UPR in a biological sample or a patient's cancer cell. In certain embodiments, the amount of the compound in the composition of the present invention is the amount that effectively induces ER stress in a biological sample or a patient's cancer cell. In certain embodiments, the amount of the compound in the composition of the present invention is the amount that effectively induces calcium release from ER via WFS1 in a biological sample or a patient's cancer cell. In certain embodiments, the composition of the present invention is prepared for administration to a patient who needs such a composition. In certain embodiments, the composition of the present invention is prepared for oral administration to a patient.

[0392] As used herein, the term "patient" refers to an animal, preferably a mammal, and most preferably a human.

[0393] 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 formulated therewith. Pharmaceutically acceptable carriers, adjuvants or vehicles that can be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, 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 silicon dioxide, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, polyethylene glycol and lanolin.

[0394] "Pharmaceutically acceptable derivative" refers to any non-toxic salt, ester, ester salt or other derivative of a compound of the invention which, upon administration to a recipient, is capable of providing, directly or indirectly, a compound of the invention or an active metabolite or residue thereof.

[0395] The term "active metabolites or residues thereof" as used herein means that the metabolites or residues thereof also cause cell death.

[0396] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the composition is administered orally, intraperitoneally, or intravenously. The sterile injectable form of the composition of the present invention can be an aqueous or oily suspension. These suspensions can be prepared using suitable dispersants or wetting agents and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic parenterally acceptable diluents or solvents, such as solutions in 1,3-butanediol. Available acceptable carriers and solvents are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are commonly used as solvents or suspending media.

[0397] For this purpose, any bland fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids (such as oleic acid and its glyceride derivatives) can be used to prepare injections, as can natural pharmaceutically acceptable oils (such as olive oil or castor oil), particularly in their polyoxyethylated forms. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other conventional surfactants (such as Tweens, Spans and other emulsifiers or bioavailability enhancers) commonly used in the preparation of pharmaceutically acceptable solids, liquids or other dosage forms can also be used to achieve the purpose of the formulation.

[0398] The pharmaceutically acceptable compositions of the present invention can be orally administered in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions, or solutions. In the case of tablets for oral use, commonly used carriers include lactose and corn starch. Lubricants, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When an aqueous suspension is required for oral use, the active ingredient is combined with an emulsifier and a suspending agent. If desired, certain sweeteners, flavorings, or coloring agents may also be added.

[0399] Alternatively, the pharmaceutically acceptable compositions of the present invention can 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 will therefore melt in the rectum to release the drug. Such materials include cocoa butter, beeswax, and polyethylene glycol.

[0400] The pharmaceutically acceptable compositions of the present invention can also be administered topically, particularly when the therapeutic target includes areas or organs readily accessible by topical administration, including diseases of the eye, skin, or lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0401] Topical application for the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or in a suitable enema formulation.Topical transdermal patches may also be used.

[0402] For topical application, the pharmaceutically acceptable compositions provided can be formulated in a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water. Alternatively, the pharmaceutically acceptable compositions provided can be formulated in a suitable lotion or cream containing the active ingredient 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.

[0403] For ophthalmic applications, provided pharmaceutically acceptable compositions can be formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, or preferably, solutions in isotonic, pH-adjusted sterile saline, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic applications, the pharmaceutically acceptable compositions can be formulated in ointments such as petrolatum.

[0404] The pharmaceutically acceptable compositions of the present invention may also be administered by nasal aerosol 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 enhance bioavailability), fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0405] Most preferably, pharmaceutically acceptable compositions of the present invention are formulated for oral administration. Such preparations can be administered with or without food. In certain embodiments, pharmaceutically acceptable compositions of the present invention are not administered with food. In other embodiments, pharmaceutically acceptable compositions of the present invention are administered with food.

[0406] The amount of the compound of the invention that can be combined with carrier materials in a single dosage form to produce a composition will vary depending on the host being treated, the particular mode of administration, etc. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0407] It will also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the specific disease being treated. The amount of the compound of the present invention in the composition will also depend on the specific compound in the composition.

[0408] Uses of compounds and pharmaceutically acceptable compositions

[0409] The compounds and compositions described herein are generally useful for treating cell proliferative disorders. As provided above, it has been found that the compounds described herein are able to activate the expression of a putative Ca2+ protein called Wolframin (WFS1). 2+ The channel triggers calcium release from the endoplasmic reticulum (ER), thereby inducing ER stress and the "unfolded protein response" (UPR), leading to cell death.

[0410] In certain embodiments, the present invention provides a method for treating a cell proliferative disorder in a patient, comprising administering a compound of the present invention or a composition comprising the compound to the patient. In certain embodiments, the present invention provides a compound of the present invention or a composition comprising the compound for treating a cell proliferative disorder. Such disorders are described in detail herein. In certain embodiments, the cell proliferative disorder is a cancer characterized by overexpression of Wolframin (WFS1) in cancer cells. In certain embodiments, the cancer characterized by overexpression of Wolframin (WFS1) is selected from non-small cell lung cancer (NSCLC), myeloma, multiple myeloma, hepatocellular carcinoma (HCC), breast cancer, bladder cancer, renal cancer, and melanoma. In certain embodiments, the method for treating a cell proliferative disorder described herein further comprises determining Wolframin (WFS1) expression levels. In certain embodiments, Wolframin (WFS1) expression levels are determined by immunohistochemistry and / or microarray probe intensity.

[0411] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder as described herein, or one or more symptoms thereof. In certain embodiments, treatment may be administered after the onset of one or more symptoms. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., taking into account a history of symptoms and / or taking into account genetic or other predisposing factors). Treatment may also be continued after symptom relief, e.g., to prevent or delay recurrence.

[0412] In certain embodiments, the present invention provides a method of inducing ER stress in a patient in need thereof, comprising administering a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention provides a method of inducing an "unfolded protein response" (UPR) in a patient in need thereof, comprising administering a compound of the present invention or a composition comprising the compound. In certain embodiments, the present invention provides a method of inducing an "unfolded protein response" (UPR) in a patient in need thereof, comprising administering a compound of the present invention or a composition comprising the compound. 2+ A method for inducing calcium release from the endoplasmic reticulum (ER) by a channel comprising administering a compound of the invention or a composition comprising the compound.

[0413] In certain embodiments, the present invention provides methods for treating a subject in need thereof via a putative Ca2+ protein called Wolframin (WFS1). 2+ In some embodiments, the present invention provides a compound of any one of Formulas I-VIII for inducing ER stress or a composition comprising the compound. In some embodiments, the present invention provides a compound of any one of Formulas I-VIII for inducing "unfolded protein response" (UPR) or a composition comprising the compound.

[0414] In certain embodiments, the present invention provides methods for treating a subject in need thereof via a putative Ca2+ protein called Wolframin (WFS1). 2+ In some embodiments, the present invention provides a compound of formula I' or a composition comprising the compound thereof for inducing calcium release from the endoplasmic reticulum (ER) through a channel. In certain embodiments, the present invention provides a compound of formula I' or a composition comprising the compound thereof for inducing ER stress in a subject in need thereof. In certain embodiments, the present invention provides a compound of formula I or a composition comprising the compound thereof for inducing an "unfolded protein response" (UPR) in a subject in need thereof.

[0415] The activity of the compounds useful as inhibitors of cell proliferation in the present invention can be assayed in vitro or in vivo. Detailed conditions for assaying the compounds of the present invention are described in the following examples.

[0416] Cell proliferative disorders

[0417] The present invention features methods and compositions for the diagnosis and prognosis of cell proliferative disorders (e.g., cancer) and the treatment of these disorders. Cell proliferative disorders described herein include, for example, cancer, obesity, and proliferation-dependent diseases. Such disorders can be diagnosed using methods known in the art.

[0418] cancer

[0419] In one embodiment, cancer includes, but is not limited to, leukemia (e.g., acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (e.g., Hodgkin's disease or non-Hodgkin's disease), Waldenstrom's macroglobulinemia, multiple myeloma , heavy chain diseases and solid tumors such as sarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's sarcoma, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, (e.g., ovarian cancer, pancreatic cancer, pancreatic cancer, ovarian cancer, bladder cancer, ovarian cancer, pancreatic cancer, ovarian cancer, ovarian cancer, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancers, gliomas, astrocytomas, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, and retinoblastoma).

[0420] In certain embodiments, the cancer is a glioma, astrocytoma, glioblastoma multiforme (GBM, also known as glioblastoma), medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, schwannoma, neurofibrosarcoma, meningioma, melanoma, neuroblastoma, or retinoblastoma.

[0421] In certain embodiments, the cancer is an acoustic neuroma, an astrocytoma (e.g., grade I - pilocytic astrocytoma, grade II - low-grade astrocytoma, grade III - anaplastic astrocytoma, or grade IV - glioblastoma (GBM)), a chordoma, a CNS lymphoma, a craniopharyngioma, a brainstem glioma, an ependymoma, a mixed glioma, an optic nerve glioma, a subependymoma, a medulloblastoma, a meningioma, a metastatic brain tumor, an oligodendroglioma, a pituitary tumor, a primitive neuroectodermal (PNET) tumor, or a schwannoma. In certain embodiments, the cancer is a type that is more common in children than in adults, such as a brainstem glioma, a craniopharyngioma, an ependymoma, a juvenile pilocytic astrocytoma (JPA), a medulloblastoma, an optic nerve glioma, a pineal tumor, a primitive neuroectodermal tumor (PNET), or a rhabdomyomas. In certain embodiments, the patient is an adult. In certain embodiments, the patient is a child or a pediatric patient.

[0422] In another embodiment, cancers include, but are not limited to, mesothelioma, hepatobiliary (liver and bile duct) cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous or intraocular melanoma, ovarian cancer, colon cancer, rectal cancer, anal cancer, stomach cancer, gastrointestinal cancer (stomach cancer, colorectal cancer), cancer of the uterus, fallopian tube, endometrium, cervix, vagina, vulva, Hodgkin's disease, esophagus, small intestine, endocrine system, thyroid, parathyroid, adrenal, soft tissue sarcoma, urethra, penis, prostate, testis, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphoma, bladder, kidney or ureter, renal cell carcinoma, renal pelvis, non-Hodgkin's lymphoma, spinal cord tumors, brain stem glioma, pituitary adenoma, adrenocortical carcinoma, gallbladder, multiple myeloma, bile duct carcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination of one or more of the foregoing cancers.

[0423] In certain 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 bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing's sarcoma; anaplastic thyroid cancer; adrenocortical adenoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0424] In certain 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, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical adenoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0425] In certain embodiments, the present invention provides a method for treating cancer that presents as a solid tumor, such as a sarcoma, carcinoma, or lymphoma, comprising the step of administering a disclosed compound or a pharmaceutically acceptable salt thereof to a patient in need thereof. Solid tumors typically include abnormal tissue masses that typically do not include cysts or fluid areas. In certain embodiments, the cancer is selected from renal cell carcinoma or kidney cancer; hepatocellular carcinoma (HCC) or hepatoblastoma or liver cancer; melanoma; breast cancer; colorectal cancer 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, ovarian epithelial cancer, ovarian cancer, or fallopian tube cancer; papillary serous cystadenocarcinoma or uterine papillary serous carcinoma (UPSC); prostate cancer; testicular cancer; gallbladder cancer; Hepatocellular carcinoma; synovial sarcoma of soft tissue and bone; rhabdomyosarcoma; osteosarcoma; chondrosarcoma; Ewing sarcoma; anaplastic thyroid cancer; adrenocortical carcinoma; pancreatic cancer; pancreatic ductal carcinoma or pancreatic adenocarcinoma; gastrointestinal / gastric (GIST) cancer; lymphoma; squamous cell carcinoma of the head and neck (SCCHN); salivary gland cancer; glioma or brain cancer; neurofibromatosis-1-associated malignant peripheral nerve sheath tumor (MPNST); Waldenstrom's macroglobulinemia; or medulloblastoma.

[0426] In certain embodiments, the cancer is selected from renal cell carcinoma, hepatocellular carcinoma (HCC), hepatoblastoma, colorectal cancer, colorectal cancer, colon cancer, rectal cancer, anal cancer, ovarian cancer, ovarian epithelial cancer, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatobiliary carcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, chondrosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, brain cancer, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0427] In certain embodiments, the cancer is selected from hepatocellular carcinoma (HCC), hepatoblastoma, colon cancer, rectal cancer, ovarian cancer, epithelial ovarian cancer, ovarian cancer, fallopian tube cancer, papillary serous cystadenocarcinoma, uterine papillary serous carcinoma (UPSC), hepatocholangiocarcinoma, synovial sarcoma of soft tissue and bone, rhabdomyosarcoma, osteosarcoma, anaplastic thyroid cancer, adrenocortical carcinoma, pancreatic cancer, pancreatic ductal carcinoma, pancreatic adenocarcinoma, glioma, neurofibromatosis-1 associated malignant peripheral nerve sheath tumor (MPNST), Waldenstrom's macroglobulinemia, or medulloblastoma.

[0428] In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In certain embodiments, the cancer is hepatoblastoma. In certain embodiments, the cancer is colon cancer. In certain embodiments, the cancer is rectal cancer. In certain embodiments, the cancer is ovarian cancer or ovarian cancer. In certain embodiments, the cancer is ovarian epithelial cancer. In certain embodiments, the cancer is fallopian tube cancer. In certain embodiments, the cancer is papillary serous cystadenocarcinoma. In certain embodiments, the cancer is uterine papillary serous carcinoma (UPSC). In certain embodiments, the cancer is hepatocholangiocarcinoma. In certain embodiments, the cancer is synovial sarcoma of soft tissue and bone. In certain embodiments, the cancer is rhabdomyosarcoma. In certain embodiments, the cancer is osteosarcoma. In certain embodiments, the cancer is anaplastic thyroid cancer. In certain embodiments, the cancer is adrenocortical carcinoma. In certain embodiments, the cancer is pancreatic cancer or pancreatic ductal carcinoma. In certain embodiments, the cancer is pancreatic adenocarcinoma. In certain embodiments, the cancer is glioma. In certain embodiments, the cancer is malignant peripheral nerve sheath tumor (MPNST). In certain embodiments, the cancer is neurofibromatosis-1 associated MPNST. In certain embodiments, the cancer is Waldenstrom's macroglobulinemia. In certain embodiments, the cancer is medulloblastoma.

[0429] The present invention further features methods and compositions for the diagnosis, prognosis, and treatment of virus-associated cancers, including human immunodeficiency virus (HIV)-associated solid tumors, human papillomavirus (HPV)-16-positive incurable solid tumors, and adult T-cell leukemias caused by human T-cell leukemia virus type 1 (HTLV-I) and characterized by clonal integration of HTLV-I in leukemic cells. A highly aggressive form of T-cell leukemia (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02631746); and virus-associated tumors in gastric, nasopharyngeal, cervical, vaginal, vulvar, head and neck squamous cell carcinoma, and Merkel cell carcinoma (see https: / / clinicaltrials.gov / ct2 / show / study / NCT02488759; see also https: / / clinicaltrials.gov / ct2 / show / study / NCT0240886; https: / / clinicaltrials.gov / ct2 / show / NCT02426892).

[0430] In certain embodiments, the present invention provides a method of treating cancer in a patient in need thereof, comprising administering to the patient any of the compounds, salts, or pharmaceutical compositions described herein. In certain embodiments, the cancer is selected from the cancers described herein. In certain embodiments, the cancer is melanoma cancer. In certain embodiments, the cancer is breast cancer. In certain embodiments, the cancer is lung cancer. In certain embodiments, the cancer is small cell lung cancer (SCLC). In certain embodiments, the cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the cancer is myeloma. In certain embodiments, the cancer is multiple myeloma. In certain embodiments, the cancer is bladder cancer. In certain embodiments, the cancer is kidney cancer. In certain embodiments, the cancer is hepatocellular carcinoma (HCC). In certain embodiments, the cancer is melanoma. In certain embodiments, the cancer is colorectal cancer. In certain embodiments, the cancer is endometrial cancer. In certain embodiments, the cancer is esophageal cancer. In certain embodiments, the cancer is pancreatic cancer. In certain embodiments, the cancer is renal cell carcinoma.

[0431] In certain embodiments, a tumor is treated by preventing further growth of the tumor. In certain embodiments, a 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 size of the tumor before treatment. In certain embodiments, a tumor is treated by reducing the amount of the tumor in the patient by at least 5%, 10%, 25%, 50%, 75%, 90%, or 99% relative to the amount of the tumor before treatment.

[0432] According to the methods of the present invention, the compounds and compositions can be administered using any amount and any route of administration that is effective for treating or alleviating the severity of a cell proliferative disorder. The exact amount required will vary between subjects, depending on the species, age, and general condition of the subject; the severity of the disease or condition; the specific agent; its mode of administration, etc. The compounds of the present invention are preferably formulated in dosage unit form for ease of administration and dosage uniformity. The expression "dosage unit form" as used herein refers to physically discrete dosage units suitable for the patient to be treated. However, it should be understood that the total daily dosage of the compounds and compositions of the present invention is determined by the attending physician within the scope of sound 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 activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex, and diet; the time of administration, route of administration, and excretion rate of the specific compound used; the duration of treatment; the drugs used in combination with or concurrently with the specific compound used and similar factors well known in the medical field. The term "patient" as used herein refers to an animal, preferably a mammal, and most preferably a human.

[0433] The pharmaceutically acceptable compositions of the present invention may be administered to humans and other animals orally, rectally, parenterally, intracisternal, intravaginal, intraperitoneally, topically (e.g., by powder, ointment, or drops), buccally, as an oral or nasal spray, etc., depending on the severity of the disease or disorder being treated. In certain embodiments, the compounds of the present invention may be administered orally or parenterally at a dosage level of about 0.01 mg / kg to about 50 mg / kg, and preferably about 1 mg / kg to about 25 mg / kg, per day, one or more times per day to achieve the desired therapeutic effect.

[0434] 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 compound, the liquid dosage form may contain an inert diluent commonly used in the art, for example, water or other solvents, solubilizers and emulsifiers such as ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (specifically, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral composition may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings, and aromatics.

[0435] According to known technology, using suitable dispersants or wetting agents and suspending agents, injectable preparations, such as sterile injectable aqueous or oily suspensions, can be prepared. The sterile injectable preparations can also be sterile injectable solutions, suspensions or emulsions in nontoxic parenteral acceptable diluents or solvents, for example as solutions in 1,3-butanediol. Among acceptable vehicles and solvents, water, Ringer's solution, USP and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are generally used as solvents or suspending media. For this purpose, any mild fixed oil can be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectable preparations.

[0436] The injectable formulations can be sterilized, for example, by filtration through a bacteria-retaining 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 prior to use.

[0437] In order to prolong the effect of the compounds of the present invention, it is often necessary to slow down the absorption of the compound from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous materials with poor water solubility. The absorption rate of the compound depends on its dissolution rate, which in turn depends on the crystal size and crystalline form. Alternatively, delayed absorption of the compound form administered parenterally can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are prepared by forming a microcapsule matrix of the compound in a biodegradable polymer (such as polylactide-polyglycolide). Depending on the ratio of the compound to the polymer and the properties of the specific polymer used, the release rate of the compound can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by encapsulating the compound in liposomes or microemulsions compatible with body tissues.

[0438] Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing a compound of this invention with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which is solid at ambient temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity and releases the active compound.

[0439] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrants such as 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 cetyl alcohol and glyceryl 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.

[0440] Similar types of solid compositions can also be used as fillers in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared using coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulation art. They can optionally contain opacifiers and can also be compositions that release the active ingredient only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Similar types of solid compositions can also be used as fillers in soft or hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols.

[0441] The active compound can also be formed into a microencapsulated form together with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shells such as enteric coatings, controlled release coatings, and other coatings well-known in the pharmaceutical formulation field. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. According to conventional practice, such dosage forms can also contain additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage form can also contain a buffer. They can optionally contain opacifiers and can also be compositions that release the active ingredient only or preferentially in a specific part of the intestinal tract, optionally in a delayed manner. Examples of usable embedding compositions include polymeric substances and waxes.

[0442] The dosage form for topical or transdermal administration of the compound of the present invention includes ointment, paste, cream, lotion, gel, powder, solution, spray, inhalant or patch. Under sterile conditions, the active ingredient is mixed with a pharmaceutically acceptable carrier and any preservative or buffer that may be needed. Ophthalmic preparations, ear drops and eye drops are also contemplated to be within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flux of the compound through the skin. By providing a rate-controlled film or by dispersing the compound in a polymer matrix or gel, the rate can be controlled.

[0443] In certain embodiments, the present invention relates to a method of inducing ER stress in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0444] In certain embodiments, the present invention relates to a method of inducing an "unfolded protein response" (UPR) in a biological sample, comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0445] In certain embodiments, the present invention relates to a method for expressing a putative Ca2+ protein in biological samples via a putative Ca2+ protein called Wolframin (WFS1). 2+ A method for causing calcium release from the endoplasmic reticulum (ER) by a channel, the method comprising the step of contacting the biological sample with a compound of the present invention or a composition comprising the compound.

[0446] As used herein, the term "biological sample" includes, but is not limited to, cell cultures or extracts thereof; biopsy material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears or other body fluids or extracts thereof.

[0447] Co-administration of additional therapeutic agents

[0448] Depending on the particular condition or disease being treated, additional therapeutic agents that are normally administered to treat that condition may also be present in the compositions of the invention. As used herein, additional therapeutic agents that are normally administered to treat a particular disease or condition are known as "appropriate for the disease or condition being treated."

[0449] In certain embodiments, the present invention provides a method of treating a disclosed disease or condition comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof and simultaneously or sequentially administering an effective amount of one or more additional therapeutic agents, such as those described herein. In certain embodiments, the method comprises co-administering one additional therapeutic agent. In certain embodiments, the method comprises co-administering two additional therapeutic agents. In certain embodiments, the combination of the disclosed compound and one or more additional therapeutic agents acts synergistically.

[0450] In certain embodiments, the additional therapeutic agent is selected from an immunostimulatory therapeutic compound. In certain embodiments, the immunostimulatory therapeutic compound is selected from evolozumab, mifamortide, an agonist or activator of a toll-like receptor, or an activator of RORγt.

[0451] In certain embodiments, the method further comprises administering to the patient a third therapeutic agent, such as an immune checkpoint inhibitor. In certain embodiments, the method comprises administering to a patient in need thereof three therapeutic agents selected from a compound disclosed herein or a pharmaceutically acceptable salt thereof, an immunostimulatory therapeutic compound, and an immune checkpoint inhibitor.

[0452] Other checkpoint inhibitors that can be used in the present invention include OX40 agonists. OX40 agonists being studied in clinical trials include: PF-04518600 / PF-8600 (Pfizer), an agonist anti-OX40 antibody for metastatic renal cancer (NCT03092856) and advanced cancers and neoplasms (NCT02554812; NCT05082566); GSK3174998 (Merck & Co.), an agonist anti-OX40 antibody in a Phase 1 cancer trial (NCT02528357); MEDI0562 (Medimmune / AstraZen) eca), 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 (NCT01862900), head and neck cancer (NCT02274155), and metastatic prostate cancer (NCT01303705); and BMS-986178 (Bristol-Myers Squibb), an agonist anti-OX40 antibody, in advanced cancers (NCT02737475).

[0453] Other checkpoint inhibitors that can be used in the present invention include CD137 (also known as 4-1BB) agonists. CD137 agonists being studied in clinical trials include: utomilumab (PF-05082566, Pfizer), an agonistic anti-CD137 antibody, for diffuse large B-cell lymphoma (NCT02951156) and advanced cancers and neoplasms (NCT02554812 and NCT05082566); urelumab (BMS-663513, Bristol-Myers Squibb), an agonistic anti-CD137 antibody, for melanoma and skin cancer (NCT02652455) and glioblastoma and gliosarcoma (NCT02658981).

[0454] Other checkpoint inhibitors that can be used in the present invention include CD27 agonists. CD27 agonists being studied in clinical trials include: venlilumab (CDX-1127, Celldex Therapeutics), an agonist anti-CD27 antibody, for squamous cell head and neck cancer, ovarian cancer, colorectal cancer, renal cell carcinoma and glioblastoma (NCT02335918); lymphoma (NCT01460134); and glioma and astrocytoma (NCT02924038).

[0455] 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 for malignant melanoma and other solid tumors (NCT01239134 and NCT02628574); GWN323 (Novartis), an agonistic anti-GITR antibody for solid tumors and lymphomas (NCT 02740270); INCAGN01876 (Incyte / Agenus), an agonistic anti-GITR antibody for advanced cancers (NCT02697591 and NCT03126110); MK-4166 (Merck & Co.), an agonistic anti-GITR antibody for solid tumors (NCT02132754); and MEDI1873 (Medimmune / AstraZeneca), an agonistic hexameric GITR-ligand molecule with a human IgG1 Fc domain for advanced solid tumors (NCT02583165).

[0456] Other checkpoint inhibitors that can be used in the present invention include inducible T-cell co-stimulator (ICOS, also known as CD278) agonists. ICOS agonists being studied in clinical trials include: MEDI-570 (Medimmune), an agonistic anti-ICOS antibody for lymphoma (NCT02520791); GSK3359609 (Merck & Co.), an agonistic anti-ICOS antibody in Phase 1 (NCT02723955); and JTX-2011 (Jounce Therapeutics), an agonistic anti-ICOS antibody in Phase 1 (NCT02904226).

[0457] Other checkpoint inhibitors that may be used in the present invention include killer IgG-like receptor (KIR) inhibitors. KIR inhibitors being studied in clinical trials include rivolumab (IPH2102 / BMS-986015, Innate Pharma / Bristol-Myers Squibb), an anti-KIR antibody, for leukemias (NCT01687387, NCT02399917, NCT02481297, NCT02599649), multiple myeloma (NCT02252263), and lymphoma (NCT01592370); IPH2101 (1-7F9, Innate Pharma), for myeloma (NCT01222286 and NCT01217203); and IPH4102 (Innate Pharma), an anti-KIR antibody that binds to three domains of the long cytoplasmic tail (KIR3DL2), for lymphoma (NCT02593045).

[0458] Other checkpoint inhibitors that can be used in the present invention include CD47 inhibitors of the interaction between CD47 and signal regulatory protein alpha (SIRPα). CD47 / SIRPa inhibitors being studied in clinical trials include: ALX-148 (Alexo Therapeutics), an antagonist variant of SIRPa that binds to CD47 and blocks CD47 / SIRPa-mediated signaling, in Phase 1 (NCT03013218); TTI-621 (SIRPa-Fc, Trillium Therapeutics), a soluble recombinant fusion protein created by linking the N-terminal CD47-binding domain of SIRPa to the Fc domain of human IgG1, which works by binding to human CD47 and preventing it from delivering its “do not eat” signal to macrophages, in Phase 1 clinical trials (NCT02890368 and NCT02663518); CC-90002 (Celgene), an anti-CD47 antibody for leukemia (NCT02641002); and Hu5F9-G4 (Forty-three Therapeutics). 7, Inc.), for colorectal neoplasms and solid tumors (NCT02953782), acute myeloid leukemia (NCT02678338), and lymphoma (NCT02953509).

[0459] 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 for solid tumors (NCT02503774); and BMS-986179 (Bristol-Myers Squibb), an anti-CD73 antibody for solid tumors (NCT02754141).

[0460] Other checkpoint inhibitors that can be used in the present invention include agonists of the stimulator of interferon genes protein (STING, also known as transmembrane protein 173 or TMEM173). STING agonists currently under investigation in clinical trials include: MK-1454 (Merck & Co.), an agonist synthetic cyclic dinucleotide, for lymphoma (NCT03010176); and ADU-S100 (MIW815, Aduro Biotech / Novartis), an agonist synthetic cyclic dinucleotide, in Phase 1 trials (NCT02675439 and NCT03172936).

[0461] 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 inhibitor of CSF1R for colorectal cancer, pancreatic cancer, metastatic and advanced cancers (NCT02777710) and melanoma, non-small cell lung cancer, squamous cell head and neck cancer, gastrointestinal stromal tumors (GIST) and ovarian cancer (NCT02452424); and IMC-CS4 (LY3022855, L illy), an anti-CSF-1R antibody, for pancreatic cancer (NCT03153410), melanoma (NCT03101254), and solid tumors (NCT02718911); and BLZ945 (4-[2((1R,2R)-2-hydroxycyclohexylamino)-benzothiazol-6-yloxy]-pyridine-2-carboxylic acid methylamide, Novartis), an orally administrable CSF1R inhibitor, for advanced solid tumors (NCT02829723).

[0462] Other checkpoint inhibitors that can be used in the present invention include NKG2A receptor inhibitors. NKG2A receptor inhibitors being studied in clinical trials include: Monalipid (IPH2201, Innate Pharma), an anti-NKG2A antibody for head and neck neoplasms (NCT02643550) and chronic lymphocytic leukemia (NCT02557516).

[0463] In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0464] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents selected from an indoleamine (2,3)-dioxygenase (IDO) inhibitor, a poly ADP-ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, a CDK4 / CDK6 inhibitor, or a phosphatidylinositol 3-kinase (PI3K) inhibitor.

[0465] In certain embodiments, the IDO inhibitor is selected from epacadostat, indoximod, capmanitib, GDC-0919, PF-06840003, BMS:F001287, Phy906 / KD108, or an enzyme that degrades kynurenine.

[0466] In certain embodiments, the PARP inhibitor is selected from olaparib, rucaparib, niraparib, iniparib, talazoparib, or veliparib.

[0467] In certain embodiments, the HDAC inhibitor is selected from vorinostat, romidepsin, panobinostat, belinostat, entinostat, or chidamide.

[0468] In certain embodiments, the CDK 4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, or trilaciclib.

[0469] In certain embodiments, the method further comprises administering to the patient a third therapeutic agent, such as an immune checkpoint inhibitor. In certain embodiments, the method comprises administering to a patient in need thereof 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 (IDO) inhibitor, 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 certain embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0470] Another immunostimulatory therapeutic that can be used in the present invention is recombinant human interleukin 15 (rhIL-15). RhIL-15 has been tested in the clinic as a therapy for melanoma and renal cell carcinoma (NCT01021059 and NCT01369888) and leukemia (NCT02689453). Another immunostimulatory therapeutic that can be used in the present invention is recombinant human interleukin 12 (rhIL-12). Another suitable IL-15-based immunotherapeutic is heterodimeric IL-15 (hetIL-15, Novartis / Admune), a fusion complex consisting of a synthetic form of endogenous IL-15 that forms a complex with a soluble IL-15 binding protein IL-15 receptor α chain (IL15:sIL-15RA), which has been tested in a Phase 1 clinical trial for melanoma, renal cell carcinoma, non-small cell lung cancer, and head and neck squamous cell carcinoma (NCT02452268). Recombinant human interleukin 12 (rhIL-12) (NM-IL-12, Neumedicines, Inc.) has been tested in the clinic for a number of oncology indications, such as as a therapy for lymphoma (NCT02544724 and NCT02542124).

[0471] In certain embodiments, the PI3K inhibitor is selected from idelalisib, alpelisib, taselisib, pictilisib, copanlisib, duvelisib, PQR309, or TGR1202.

[0472] In another aspect, the present invention provides a method of treating cancer in a patient in need thereof, wherein the method comprises administering to the patient a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more additional therapeutic agents selected from platinum-based therapeutics, taxanes, nucleoside inhibitors, or therapeutic agents that interfere with normal DNA synthesis, protein synthesis, cell replication, or would otherwise inhibit rapidly proliferating cells.

[0473] In certain embodiments, the platinum-based therapeutic is selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, picoplatin, or satraplatin.

[0474] In certain embodiments, the taxane is selected from paclitaxel, docetaxel, albumin-bound paclitaxel, cabazitaxel, or SID530.

[0475] In certain embodiments, the therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or would otherwise interfere with the replication of rapidly proliferating cells is selected from trabectedin, nitrogen mustard, vincristine, temozolomide, cytarabine, lomustine, azacitidine, omacetaxine mepesuccinate, asparaginase Erwinia chrysnthemi, eribulin mesylate, capacetrine, bendamustine, ixabepilone, nelarabine, clorafabine, trifluridine, or tipiracil.

[0476] In certain embodiments, the method further comprises administering to the patient a third therapeutic agent, such as an immune checkpoint inhibitor. In certain embodiments, the method comprises administering to a patient in need thereof three therapeutic agents selected from: a compound disclosed herein or a pharmaceutically acceptable salt thereof, a second therapeutic agent 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 will otherwise inhibit rapidly proliferating cells, and a third therapeutic agent selected from an immune checkpoint inhibitor.

[0477] In certain embodiments, the immune checkpoint inhibitor is selected from nivolumab, pembrolizumab, ipilimumab, avelumab, durvalumab, atezolizumab, or pidilizumab.

[0478] In certain 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-associated biomarker.

[0479] In certain embodiments, the biological sample is a blood sample.

[0480] In certain embodiments, the disease-associated biomarker is selected from circulating CD8+ T cells or the ratio of CD8+ T cells to Treg cells.

[0481] On the one hand, the present invention provides a method for treating advanced cancer, comprising administering a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof, as a single agent (monotherapy) or in combination with a chemotherapeutic agent, a targeted therapeutic agent such as a kinase inhibitor, and / or an immunomodulatory therapy such as an immune checkpoint inhibitor. In certain embodiments, the immune checkpoint inhibitor is an antibody to PD-1. PD-1 binds to the programmed cell death 1 receptor (PD-1) to prevent the receptor from binding to the inhibitory ligand PDL-1, thereby hindering the tumor's ability to suppress the host's anti-tumor immune response.

[0482] In certain embodiments, the additional therapeutic agent is a kinase inhibitor or a VEGF-R antagonist. Approved VEGF inhibitors and kinase inhibitors useful in the present invention include: bevacizumab ( Genentech / Roche), an anti-VEGF monoclonal antibody; ramucirumab ( Eli Lilly), an anti-VEGFR-2 antibody; and ziv-aflibercept, also known as VEGF Trap ( Regeneron / Sanofi). VEGFR inhibitors, such as regorafenib ( Bayer); Fantanib ( AstraZeneca; Axitinib ( Pfizer; and lenvatinib ( Eisai); Raf inhibitors, such as sorafenib ( Bayer AG and Onyx); dabrafenib ( Novartis); and vemurafenib ( Genentech / Roche); MEK inhibitors such as cobimetanib ( Exelexis / Genentech / Roche); trametinib ( Novartis); Bcr-Abl tyrosine kinase inhibitors such as imatinib ( Novartis; Nilotinib ( Novartis; dasatinib ( BristolMyersSquibb; Bosutinib ( Pfizer; and ponatinib ( Ariad Pharmaceuticals); Her2 and EGFR inhibitors, such as gefitinib ( AstraZeneca; Erlotinib ( Genentech / Roche / Astellas); Lapatinib ( Novartis; afatinib ( Boehringer Ingelheim; osimertinib (targeting activated EGFR, AstraZeneca; and brigatinib ( Ariad Pharmaceuticals); c-Met and VEGFR2 inhibitors, such as cabozantinib ( Exelexis); and multikinase inhibitors, such as sunitinib ( Pfizer; Pazopanib ( Novartis); ALK inhibitors, such as crizotinib ( Pfizer; Ceritinib ( Novartis); and alectinib ( Genentech / Roche); Bruton's tyrosine kinase inhibitors, such as ibrutinib ( Pharmacyclics / Janssen); and Flt3 receptor inhibitors, such as midostaurin ( Novartis).

[0483] Other kinase inhibitors and VEGF-R antagonists in development and that may be used in the present invention include: tivozanib (Aveo Pharmaceuticals); varanib (Bayer / Novartis); lucitanib (Clovis Oncology); duvitinib (TKI258, Novartis); chiauanib (Chipscreen Biosciences); CEP-11981 (Cephalon); linifanib (Abbott Laboratories); neratinib (HKI-272, Puma Biotechnology); radotinib ( IY5511, Il-Yang Pharmaceuticals, S.Korea); Ruxolitinib ( Incyte Corporation); PTC299 (PTC Therapeutics); CP-547,632 (Pfizer); foretinib (Exelexis, GlaxoSmithKline); quizartinib (Daiichi Sankyo) and motesanib (Amgen / Takeda).

[0484] In certain 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 ( Novartis); Temsirolimus ( Pfizer); and sirolimus ( Pfizer).

[0485] In certain embodiments, the additional therapeutic agent is a poly ADP ribose polymerase (PARP) inhibitor. Approved PARP inhibitors useful in the present invention include: Lynparza ( AstraZeneca; rucaparib ( Clovis Oncology; and niraparib ( Other PARP inhibitors under investigation 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.).

[0486] In certain embodiments, the additional therapeutic agent is a phosphatidylinositol 3-kinase (PI3K) inhibitor. Approved PI3K inhibitors useful in the present invention include idelalisib ( Other PI3K inhibitors under investigation that may be used in the present invention include: apellisib (BYL719, Novartis); taselisib (GDC-0032, Genentech / Roche); pikrisib (GDC-0941, Genentech / Roche); kupanisib (BAY806946, Bayer); davilisib (formerly IPI-145, Infinity Pharmaceuticals); PQR309 (Piqur Therapeutics, Switzerland); and TGR1202 (formerly RP5230, TG Therapeutics).

[0487] In certain embodiments, the additional therapeutic agent is a proteasome inhibitor. Approved proteasome inhibitors useful in the present invention include: bortezomib ( Takeda); Carfilzomib ( Amgen); and ixazomib ( Takeda).

[0488] In certain embodiments, the additional therapeutic agent is a histone deacetylase (HDAC) inhibitor. Approved HDAC inhibitors useful in the present invention include: Vorinostat ( Merck & Co.); Romidepsin ( Celgene); Panobinostat ( Novartis); and belinostat ( Spectrum Pharmaceuticals). Other HDAC inhibitors under investigation that may be used in the present invention include: entinostat (SNDX-275, Syndax Pharmaceuticals) (NCT00866333); and chidamide ( HBI-8000, Chipscreen Biosciences, China).

[0489] In certain embodiments, the additional therapeutic agent is a CDK inhibitor, such as a CDK4 / 6 inhibitor. Approved CDK 4 / 6 inhibitors useful in the present invention include: Palbociclib ( Pfizer; and ribociclib ( Other CDK 4 / 6 inhibitors under investigation that may be used in the present invention include abemaciclib (Ly2835219, Eli Lilly) and trilaciclib (G1T28, G1 Therapeutics).

[0490] In certain embodiments, the additional therapeutic agent is an indoleamine (2,3)-dioxygenase (IDO) inhibitor. Investigational IDO inhibitors that may be used in the present invention include: icardostat (INCB024360, Incyte); dosimod (NLG-8189, NewLink Genetics Corporation); capratinib (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).

[0491] In certain 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 ( Eli Lilly). Approved EGFR antagonists that can be used in the present invention include: Cetuximab ( Eli Lilly; Nexilimumab ( Eli Lilly), panitumumab ( Amgen); and osimertinib (targeting activated EGFR, AstraZeneca).

[0492] In certain embodiments, the additional therapeutic agent is an aromatase inhibitor. Approved aromatase inhibitors that can be used in the present invention include: exemestane ( Pfizer; anastazole ( AstraZeneca and letrozole ( Novartis).

[0493] In certain embodiments, the additional therapeutic agent is an antagonist of the hedgehog pathway. Approved hedgehog pathway inhibitors that can be used in the present invention include: sonidegib ( Sun Pharmaceuticals; and vismodegib ( Genentech), both used to treat basal cell carcinoma.

[0494] In certain embodiments, the additional therapeutic agent is a folate inhibitor. Approved folate inhibitors useful in the present invention include pemetrexed ( Eli Lilly).

[0495] In certain embodiments, the additional therapeutic agent is a CC chemokine receptor 4 (CCR4) inhibitor. Investigational CCR4 inhibitors that may be useful in the present invention include mogamulizumab ( Kyowa Hakko Kirin, Japan).

[0496] In certain embodiments, the additional therapeutic agent is an isocitrate dehydrogenase (IDH) inhibitor. IDH inhibitors under investigation that can be used in the present invention include: AG120 (Celgene; NCT02677922); AG221 (Celgene, NCT02677922; NCT02577406); BAY1436032 (Bayer, NCT02746081); IDH305 (Novartis, NCT02987010).

[0497] In certain embodiments, the additional therapeutic agent is an arginase inhibitor. Arginase inhibitors under investigation that can be used in the present invention include: AEB1102 (PEGylated recombinant 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 CB-1158 (Calithera Biosciences).

[0498] In certain embodiments, the additional therapeutic agent is a glutaminase inhibitor. Glutaminase inhibitors under investigation that may be used in the present invention include CB-839 (Calithera Biosciences).

[0499] In certain embodiments, the additional therapeutic agent is an antibody that binds to a tumor antigen (i.e., a protein expressed on the cell surface of a tumor cell). Approved antibodies that bind to tumor antigens that can be used in the present invention include: Rituximab ( Genentech / Biogen Idec; ofatumumab (anti-CD20, GlaxoSmithKline); Atezolizumab (anti-CD20, Genentech), Ibritumomab (anti-CD20 and Yttrium-90, Spectrum Pharmaceuticals); Daratumumab (anti-CD38, Janssen Biotech), dinutuximab (anti-glycolipid GD2, United Therapeutics; Trastuzumab (anti-HER2, Genentech); ado-trastuzumab emtansine (anti-HER2 fused to emtansine) Genentech); and pertuzumab (anti-HER2, Genentech); and brentuximab vedotin (anti-CD30-drug conjugate, Seattle Genetics).

[0500] In certain embodiments, the additional therapeutic agent is a topoisomerase inhibitor. Approved topoisomerase inhibitors useful in the present invention include irinotecan ( Merrimack Pharmaceuticals); topotecan ( GlaxoSmithKline). Topoisomerase inhibitors under investigation that may be used in the present invention include pixenol ( CTI Biopharma).

[0501] In certain embodiments, the additional therapeutic agent is a nucleoside inhibitor or other therapeutic agent that interferes with normal DNA synthesis, protein synthesis, cell replication, or would otherwise inhibit rapidly proliferating cells. Such nucleoside inhibitors or other therapeutic agents include: trabectedin (a guanylating agent, Janssen Oncology), nitrogen mustard (alkylating agent, Aktelion Pharmaceuticals); vincristine ( Eli Lilly; Teva Pharmaceuticals; Talon Therapeutics); Temozolomide (a prodrug of the alkylating agent 5-(3-methyltriazene-1-yl)-imidazole-4-carboxamide (MTIC), Merck & Co.); cytarabine injection (cytarabine, an antimetabolite cytidine analog, Pfizer); lomustine (an alkylating agent, Bristol-MyersSquibb; NextSource Biotechnology); azacitidine (a pyrimidine nucleoside analog of cytidine, Celgene; omacetaxine mepesuccinate (omacetaxine mepesuccinate) (protein synthesis inhibitor, Teva Pharmaceuticals); asparaginase from Erwinia chrysanthemi (an enzyme used to deplete asparagine, Lundbeck; EUSA Pharma); Eribulin mesylate (microtubule inhibitor, tubulin-based antimitotic agent, Eisai); Cabazitaxel (microtubule inhibitor, tubulin-based antimitotic agent, Sanofi-Aventis); Capecitabine (thymidylate synthase inhibitor, Genentech); bendamustine (a bifunctional nitrogen mustard derivative believed to form interstrand DNA crosslinks, Cephalon / Teva); Ixabepilone (a semisynthetic analog of epothilone B, a microtubule inhibitor, a tubulin-based antimitotic agent, Bristol-Myers Squibb); Nelarabine (a prodrug of a deoxyguanosine analog, a nucleoside metabolism inhibitor, Novartis); Clofarabine (a prodrug of a ribonucleotide reductase inhibitor, a competitive inhibitor of deoxycytidine, Sanofi-Aventis); and trifluridine and dipivefrin (thymidine-based nucleoside analogs and thymidine phosphorylase inhibitors, Taiho Oncology).

[0502] In certain embodiments, the additional therapeutic agent is a platinum-based therapeutic agent, also known as platins. Platinums cause cross-linking of DNA, causing them to inhibit DNA repair and / or DNA synthesis, primarily in rapidly reproducing cells, such as cancer cells. Approved platinum-based therapeutic agents that can be used in the present invention include: cisplatin ( Bristol-Myers Squibb); Carboplatin ( Bristol-Myers Squibb; and, Teva; Pfizer); oxaliplatin ( Sanofi-Aventis); and nedaplatin ( Shionogi. Other platinum-based therapeutics that have undergone clinical trials and may be used in the present invention include: picoplatin (Poniard Pharmaceuticals) and satraplatin (JM-216, Agennix).

[0503] In certain embodiments, the additional therapeutic agent is a taxane compound that causes the disruption of microtubules necessary for cell division. Approved taxane compounds that can be used in the present invention include: Paclitaxel ( Bristol-Myers Squibb, docetaxel ( Sanofi-Aventis; SunPharmaceutical), albumin-bound paclitaxel ( Abraxis / Celgene) and cabazitaxel ( Sanofi-Aventis. Other taxane compounds that have undergone clinical trials and can be used in the present invention include SID530 (SK Chemicals, Co.) (NCT00931008).

[0504] In certain embodiments, the additional therapeutic agent is an inhibitor of an anti-apoptotic protein, such as BCL-2. Approved anti-apoptotic agents that can be used in the present invention include: venetoclax ( AbbVie / Genentech); and rantuzumab ( Other therapeutic agents targeting apoptotic proteins that have undergone clinical trials and can be used in the present invention include navitoclax (ABT-263, Abbott), a BCL-2 inhibitor (NCT02079740).

[0505] In certain embodiments, the present invention provides a method of treating prostate cancer comprising administering to a patient in need thereof an effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, 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 ( Astellas / Medivation); approved androgen synthesis inhibitors, including abiraterone ( Centocor / Ortho); approved gonadotropin-releasing hormone (GnRH) receptor antagonists (degaralix, Ferring Pharmaceuticals).

[0506] In certain embodiments, the additional therapeutic agent is a selective estrogen receptor modulator (SERM), which interferes with the synthesis or activity of estrogen. Approved SERMs useful in the present invention include raloxifene ( Eli Lilly).

[0507] In certain embodiments, the additional therapeutic agent is a bone resorption inhibitor. Approved therapeutic agents that inhibit bone resorption are denosumab ( Amgen), an antibody that binds to RANKL and prevents binding to its receptor RANK found on the surface of osteoclasts, their precursors, and osteoclast-like giant cells, which mediates bone pathology in solid tumors with bone metastases. Other approved therapeutic agents that inhibit bone resorption include bisphosphonates, such as zoledronic acid ( Novartis).

[0508] In certain embodiments, the additional therapeutic agent is an inhibitor of the interaction between two primary p53 inhibitory proteins MDMX and MDM2. Inhibitors of p53 inhibitory proteins under investigation that can be used in the present invention include: ALRN-6924 (Aileron), which is a stapled peptide that equivalently binds to and disrupts the interaction of MDMX and MDM2 with p53. ALRN-6924 (NCT02909972; NCT02264613) is currently being evaluated in clinical trials for the treatment of AML, advanced myelodysplastic syndrome (MDS), and peripheral T-cell lymphoma (PTCL).

[0509] In certain embodiments, the additional therapeutic agent is an inhibitor of transforming growth factor-beta (TGF-β or TGFβ). Inhibitors of TGF-β proteins under investigation that can be used in the present invention include: NIS793 (Novartis), an anti-TGF-β antibody (NCT 02947165), which is in clinical trials for the treatment of various cancers, including breast cancer, lung cancer, hepatocellular carcinoma, colorectal cancer, pancreatic cancer, prostate cancer, and kidney cancer. In certain embodiments, the inhibitor of TGF-β protein is fusumab (GC1008; Sanofi-G enzyme), which is being studied for melanoma (NCT00923169); renal cell carcinoma (NCT00356460); and non-small cell lung cancer (NCT02581787). Additionally, in certain embodiments, the additional therapeutic agent is a TGF-β trap, such as described in Connolly et al. (2012) Int'l J. Biological Sciences 8:964-978.

[0510] Additional co-administered therapeutic agents - targeted therapeutics and immunomodulatory drugs

[0511] In certain embodiments, the additional therapeutic agent is selected from a targeted therapeutic or an immunomodulatory drug.Adjuvant therapy using targeted therapeutics or immunomodulatory drugs has shown promising efficacy when administered alone, but is limited by the development of tumor immunity or immune response evasion over time.

[0512] In certain embodiments, the present invention provides a method of treating cancer (such as the cancers described herein) comprising administering to a patient in need thereof an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in combination with an additional therapeutic agent such as a targeted therapeutic agent or an immunomodulatory drug. In certain embodiments, the immunomodulatory therapeutic specifically induces apoptosis in tumor cells. Approved immunomodulatory therapeutics that can be used in the present invention include: pomalidomide ( Celgene; Lenalidomide ( Celgene; ingenol mebutate ( LEO Pharma).

[0513] In other embodiments, the immunomodulatory therapeutic agent is a cancer vaccine. In certain embodiments, the cancer vaccine is selected from sipuleucel-T ( Dendreon / Valeant Pharmaceuticals), which has been approved for the treatment of asymptomatic or minimally symptomatic metastatic castration-resistant (hormone-refractory) prostate cancer; and talimogene laherparepvec ( BioVex / Amgen, formerly known as T-VEC), a genetically modified oncolytic virus therapy approved for the treatment of unresectable skin, subcutaneous, and lymph node lesions in melanoma. In certain embodiments, the additional therapeutic agent is selected from oncolytic virus therapies such as pexastimogene devaccinepvec (PexaVec / JX-594, SillaJen / formerly Jennerex Biotherapeutics), a thymidine kinase- (TK-)-deficient vaccinia virus engineered to express GM-CSF for hepatocellular carcinoma (NCT02562755) and melanoma (NCT00429312); pelareorep ( Oncolytics Biotech, a variant of the respiratory enteric orphan virus (reovirus) that does not replicate in non-RAS-activated cells, is being investigated for a number of cancers, including colorectal cancer (NCT01622543); prostate cancer (NCT01619813); head and neck squamous cell carcinoma (NCT01166542); pancreatic adenocarcinoma (NCT00998322); and non-small cell lung cancer (NSCLC) (NCT 00861627); enadenotucirev (NG-348, PsiOxus, formerly ColoAd1), an adenovirus engineered to express full-length CD80 and an antibody fragment specific for the T-cell receptor CD3 protein, for ovarian cancer (NCT02028117); metastatic or advanced epithelial tumors such as colorectal cancer, bladder cancer, head and neck squamous cell carcinoma, and salivary gland cancer (NCT02636036); ONCOS-102 (Targovax / formerly Oncos), an adenovirus engineered to express GM-CSF, is being studied for melanoma (NCT03003676); and peritoneal disease, colorectal cancer, or ovarian cancer (NCT02963831); GL-ONC1 (GLV-1h68 / GLV-1h153, Genelux GmbH), a vaccinia virus engineered to express β-galactosidase (β-gal) / β-glucuronidase or β-gal / human sodium iodide symporter (hNIS), respectively, is being studied for peritoneal carcinomatosis (NCT01443260); fallopian tube cancer, and ovarian cancer (NCT02759588); or CG0070 (Cold Genesys), an adenovirus engineered to express GM-CSF, is being studied for bladder cancer (NCT02365818).

[0514] In certain embodiments, the additional therapeutic agent is selected from JX-929 (SillaJen / formerly Jennerex Biotherapeutics), a TK- and vaccinia growth factor-deficient vaccinia virus engineered to express cytosine deaminase, which is capable of converting the prodrug 5-fluorocytosine to the cytotoxic drug 5-fluorouracil; TG01 and TG02 (Targovax / formerly Oncos), which are peptide-based immunotherapeutics targeting refractory RAS mutations; and TILT-123 (TILT Biotherapeutics), an engineered adenovirus designated Ad5 / 3-E2F-δ24-hTNFα-IRES-hIL20; and VSV-GP (ViraTherapeutics), a vesicular stomatitis virus (VSV) engineered to express the glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV), which can be further engineered to express antigens designed to generate antigen-specific CD8 + T cell response.

[0515] In certain embodiments, the present invention includes administering a compound disclosed herein or a pharmaceutically acceptable salt thereof to the patient in combination with T-cells engineered to express a chimeric antigen receptor or CAR. T-cells engineered to express such a chimeric antigen receptor are referred to as CAR-T cells.

[0516] A CAR consisting of a binding domain has been constructed that can be derived from a natural ligand, a single-chain variable fragment (scFv) derived from a monoclonal antibody specific for a cell surface antigen, fused to an intracellular domain as the functional end of a T cell receptor (TCR), such as the CD3-ζ signaling domain from TCR, which is capable of generating an activation signal in T lymphocytes. After antigen binding, such a CAR is connected to the endogenous signaling pathway in the effector cell and generates an activation signal similar to that initiated by the TCR complex.

[0517] For example, in certain embodiments, CAR-T cells are one of the cells described in U.S. Patent No. 8,906,682 (June; hereby incorporated by reference in its entirety), which discloses CAR-T cells engineered to include an extracellular domain having an antigen binding domain (such as a domain that binds CD19) fused to an intracellular signaling domain of the ζ chain of the T cell antigen receptor complex (such as CD3ζ). When expressed in T cells, CAR is able to redirect antigen recognition based on antigen binding specificity. In the case of CD19, the antigen is expressed on malignant B cells. Currently, more than 200 clinical trials are underway using CAR-T for a variety of indications. [https: / / clinicaltrials.gov / ct2 / results?term=chimeric+antigen+receptors&pg=1].

[0518] Additional co-administered therapeutic agents - immunostimulatory drugs

[0519] In certain embodiments, the additional therapeutic agent is an immunostimulatory drug. For example, antibodies that block the PD-1 and PD-L1 inhibitory axis can release activated tumor-reactive T cells and have been shown in clinical trials to induce durable anti-tumor responses in a growing number of tumor histologies, including some tumor types that have not traditionally been considered sensitive to immunotherapy. See, for example, Okazaki, T. et al. (2013) Nat. Immunol. 14, 1212-1218; Zou et al. (2016) Sci. Transl. Med. 8. The anti-PD-1 antibody nivolumab ( Bristol-Myers Squibb (also known as ONO-4538, MDX1106, and BMS-936558) has shown the potential to improve overall survival in RCC patients who experience disease progression during or after prior anti-angiogenic therapy.

[0520] In certain embodiments, the present invention provides a method for treating cancer (such as cancer described herein), which includes administering an effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a patient in need thereof in combination with an additional therapeutic agent such as an immunostimulatory drug such as an immune checkpoint inhibitor. In certain embodiments, the compound and the checkpoint inhibitor are administered simultaneously or sequentially. In certain embodiments, the compound disclosed herein is administered prior to the initial administration of an immune checkpoint inhibitor. In certain embodiments, an immune checkpoint inhibitor is administered prior to the initial administration of a compound disclosed herein.

[0521] In certain embodiments, the immune checkpoint inhibitor is selected from a PD-1 antagonist, a PD-L1 antagonist, or a CTLA-4 antagonist. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are administered in combination with the following agents: nivolumab (anti-PD-1 antibody, Bristol-Myers Squibb; Pembrolizumab (anti-PD-1 antibody, Merck & Co.); Ipilimumab (anti-CTLA-4 antibody, Bristol-Myers Squibb; Durvalumab (anti-PD-L1 antibody, AstraZeneca); or atezolizumab (anti-PD-L1 antibody, Genentech).

[0522] Other immune checkpoint inhibitors suitable for use in the present invention include: REGN2810 (Regeneron), an anti-PD-1 antibody being tested in patients with basal cell carcinoma (NCT03132636), NSCLC (NCT03088540), cutaneous squamous cell carcinoma (NCT02760498), lymphoma (NCT02651662), and melanoma (NCT03002376); pidilizumab (CureTech), also known as CT-011, an antibody that binds to PD-1 in clinical trials for diffuse large B-cell lymphoma and multiple myeloma; avelumab ( Pfizer / Merck KGaA), also known as MSB0010718C), a fully human IgG1 anti-PD-L1 antibody in clinical trials for non-small cell lung cancer, Merkel cell carcinoma, mesothelioma, solid tumors, renal cancer, ovarian cancer, bladder cancer, head and neck cancer, and gastric cancer; and PDR001 (Novartis), an inhibitory antibody that binds 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, renal cancer, breast cancer, lung cancer, and non-small cell lung cancer, pancreatic ductal adenocarcinoma, pancreatic cancer, germ cell cancer, head and neck squamous cell carcinoma, hepatocellular carcinoma, prostate cancer, endometrial cancer, metastatic cancer in the liver, liver cancer, large B-cell lymphoma, 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 a Phase 1 clinical trial for advanced solid tumors (NCT02694822).

[0523] Another example of immune stimulation is the use of oncolytic viruses. In certain 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 immune stimulating therapy such as an oncolytic virus. Approved immune stimulating oncolytic viruses that can be used in the present invention include talimogene laherparepvec (live attenuated herpes simplex virus, Amgen).

[0524] In certain embodiments, the additional therapeutic agent is an activator of retinoic acid receptor-related orphan receptor gamma (RORγt). RORγt is a transcription factor that plays a key role in the differentiation and maintenance of type 17 effector subsets of CD4+ (Th17) and CD8+ (Tc17) T cells and the differentiation of innate immune cell subsets such as NK cells that express IL-17. The activator of RORγt under study that can be used in the present invention is LYC-55716 (Lycera), which is currently being evaluated in clinical trials for the treatment of solid tumors (NCT02929862).

[0525] In certain embodiments, the additional therapeutic agent is an agonist or activator of a toll-like receptor (TLR). Suitable TLR activators include agonists or activators of TLR9 such as SD-101 (Dynavax). SD-101 is an immunostimulatory CpG that is under investigation for B-cells, follicular and other lymphomas (NCT02254772). Agonists or activators of TLR8 that can be used in the present invention include motolimod (VTX-2337, VentiRx Pharmaceuticals), which is under investigation for head and neck squamous cell carcinoma (NCT02124850) and ovarian cancer (NCT02431559).

[0526] Other checkpoint inhibitors that can be used in the present invention include inhibitors of T-cell immunoglobulin mucin (TIM-3) containing protein-3. TIM-3 inhibitors that can be used in the present invention include TSR-022, LY3321367, and MBG453. TSR-022 (Tesaro) is an anti-TIM-3 antibody that is being studied in solid tumors (NCT02817633). LY3321367 (Eli Lilly) is an anti-TIM-3 antibody that is being studied in solid tumors (NCT03099109). MBG453 (Novartis) is an anti-TIM-3 antibody that is being studied in advanced malignancies (NCT02608268).

[0527] Other checkpoint inhibitors that can be used in the present invention include inhibitors of T cell immunoreceptors with Ig and ITIM domains, or inhibitors of TIGIT (i.e., an immunoreceptor 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 anti-TIGIT monoclonal antibody (NCT03119428).

[0528] Checkpoint inhibitors that can be used in the present invention also include inhibitors of lymphocyte activation gene-3 (LAG-3). LAG-3 inhibitors that can be used in the present invention include BMS-986016, REGN3767, and IMP321. BMS-986016 (Bristol-Myers Squibb), an anti-LAG-3 antibody, is being studied in glioblastoma and gliosarcoma (NCT02658981). REGN3767 (Regeneron) is also an anti-LAG-3 antibody that is being studied in malignant tumors (NCT03005782). IMP321 (Immutep SA) is a LAG-3-Ig fusion protein that is being studied in melanoma (NCT02676869), adenocarcinoma (NCT02614833), and metastatic breast cancer (NCT00349934).

[0529] Other immuno-oncology agents that can be used in the present invention in combination with the compounds disclosed herein include: urelumab (BMS-663513, Bristol-Myers Squibb), an anti-CD137 monoclonal antibody; valeronumab (CDX-1127, Celldex Therapeutics), an anti-CD27 monoclonal antibody; BMS-986178 (Bristol-Myers Squibb), an anti-OX40 monoclonal antibody; rilumab (IPH2102 / BMS-986015, InnatePharma, Bristol-Myers Squibb), an anti-KIR monoclonal antibody; monalizumab (IPH2201, Innate Pharma, AstraZeneca), an anti-NKG2A monoclonal antibody; and ancaliximab (GS-5745, Gilead Sciences), an anti-MMP9 antibody; and MK-4166 (Merck & Co.), an anti-GITR monoclonal antibody.

[0530] Other additional therapeutic agents that can be used in the present invention include glembatumumab vedotin-monomethyl auristatin E (MMAE) (Celldex), an anti-glycoprotein NMB (gpNMB) antibody (CR011) linked to the cytotoxic MMAE. gpNMB is a protein overexpressed by various tumor types that is associated with the metastatic ability of cancer cells.

[0531] The compounds of the present invention may also be used in combination with other anti-proliferative compounds to produce advantages. Such anti-proliferative 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 cell differentiation processes; cyclooxygenase inhibitors; MMP inhibitors; mTOR inhibitors; anti-tumor antimetabolites; platinum compounds; compounds that target / reduce the activity of protein or lipid kinases and additional anti-angiogenic compounds; compounds that target, reduce or inhibit the activity of protein or lipid phosphatases; gonadotropin-releasing hormone agonists; antiandrogens; methionine aminopeptidase inhibitors; matrix metalloproteinases inhibitors; bisphosphonates; biological response modifiers; antiproliferative antibodies; heparanase inhibitors; inhibitors of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds for the treatment of hematological malignancies; compounds that target, decrease, or inhibit Flt-3 activity; Hsp90 inhibitors such as 17-AAG (17-allylaminogeldanamycin, NSC330507), 17-DMAG (17-dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010 (from Conforma Therapeutics); temozolomide Kinesin spindle protein inhibitors, such as SB715992 or SB743921 (from GlaxoSmithKline), or pentamidine / chlorpromazine (from CombinatoRx); MEK inhibitors such as ARRY142886 (from Array BioPharma), AZd6244 (from AstraZeneca), PD181461 (from Pfizer) and folinic acid.

[0532] The term "checkpoint inhibitor" as used herein refers to agents that can be used to prevent cancer cells from evading the patient's immune system. One of the main mechanisms of anti-tumor immune subversion is called "T cell exhaustion," which is caused by persistent antigen exposure that has led to the upregulation of inhibitory receptors. These inhibitory receptors act as immune checkpoints to prevent uncontrolled immune responses.

[0533] PD-1 and co-inhibitory receptors 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), and lymphocyte activation gene-3 (Lag-3; CD223) are often referred to as checkpoint regulators. They act as molecular "gatekeepers" that allow extracellular information to dictate whether cell cycle progression and other intracellular signaling processes should proceed.

[0534] In one aspect, the checkpoint inhibitor is a biotherapeutic agent or a 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 another aspect, the checkpoint inhibitor inhibits a checkpoint protein selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In another aspect, the checkpoint inhibitor interacts with a checkpoint protein ligand selected from CTLA-4, PDL1, PDL2, PD1, B7-H3, B7-H4, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, CGEN-15049, CHK 1, CHK2, A2aR, B-7 family ligand, or a combination thereof. In one aspect, the checkpoint inhibitor is an immunostimulant, a T cell growth factor, an interleukin, an antibody, a vaccine, or a combination thereof. In another aspect, the interleukin is IL-7 or IL-15. In a specific aspect, the interleukin is a glycosylated IL-7. In another aspect, the vaccine is a dendritic cell (DC) vaccine.

[0535] Checkpoint inhibitors include any agent that blocks or inhibits the inhibitory pathway of the immune system in a statistically significant manner. Such inhibitors may include small molecule inhibitors, or may include antibodies or antigen binding fragments thereof that bind to and block or inhibit immune checkpoint receptors, or antibodies that bind to and block or inhibit immune checkpoint receptor ligands. Exemplary checkpoint molecules that can be targeted for blocking 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 present in all NK, γδ and memory CD8 +(αβ) T cells), CD160 (also known as BY55), CGEN-15049, CHK1 and CHK2 kinases, A2aR, and various B-7 family ligands. B7 family ligands include, but are not limited to, B7-1, B7-2, B7-DC, B7-H1, B7-H2, B7-H3, B7-H4, B7-H5, B7-H6, and B7-H7. Checkpoint inhibitors include antibodies, or antigen-binding fragments thereof, other binding proteins, biotherapeutics, or small molecules that bind to and block or inhibit the activity of one or more of the following: CTLA-4, PDL1, PDL2, PD1, BTLA, HVEM, TIM3, GAL9, LAG3, VISTA, KIR, 2B4, CD160, and CGEN-15049. Exemplary immune checkpoint inhibitors include tremelimumab (CTLA-4 blocking antibody), anti-OX40, PD-L1 monoclonal antibody (anti-B7-H1; MEDI4736), MK-3475 (PD-1 blocker), nivolumab (anti-PD1 antibody), CT-011 (anti-PD1 antibody), BY55 monoclonal antibody, AMP224 (anti-PDL1 antibody), BMS-936559 (anti-PDL1 antibody), MPLDL3280A (anti-PDL1 antibody), MSB0010718C (anti-PDL1 antibody) 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.

[0536] In certain embodiments, the immune checkpoint inhibitor is selected from PD-1 antagonists, PD-L1 antagonists, and CTLA-4 antagonists. In certain embodiments, the checkpoint inhibitor is selected from nivolumab. Ipilimumab and pembrolizumab

[0537] In certain embodiments, the checkpoint inhibitor is selected from lambrolizumab (MK-3475), nivolumab (BMS-936558), pidilizumab (CT-011), AMP-224, MDX-1105, MEDI4736, MPDL3280A, BMS-936559, ipilimumab, lirlumab, IPH2101, pembrolizumab and tremelimumab.

[0538] The term "aromatase inhibitor" as used herein relates to compounds that inhibit the production of estrogens, for example the conversion of the substrates androstenedione and testosterone to estrone and estradiol, respectively. The term includes, but is not limited to, steroids, in particular atamestane, exemestane and formestane, and in particular non-steroids, in particular aminoglutethimide, lotrakide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole and letrozole. Exemestane is commercially available under the name anostane. TM (Aromasin TM Formestane is sold under the trade name Lentaron TM Fadrozole is sold under the trade name Afema TM Anastrozole is sold under the trade name Arimidex. TM Letrozole is sold under the trade name Flon TM or Femar TM Aminglutethimide is sold under the trade name Orimeten TM The combinations of the invention comprising a chemotherapeutic agent which is an aromatase inhibitor are particularly useful in the treatment of hormone receptor positive tumors, such as breast tumors.

[0539] As used herein, the term "antiestrogen" refers to compounds that antagonize the effects 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. TM Raloxifene hydrochloride is sold under the trade name Evita TM Fulvestrant is sold under the trade name Faslodex TM The combinations of the invention comprising a chemotherapeutic agent which is an antiestrogen are particularly useful in the treatment of estrogen receptor positive tumors, such as breast tumors.

[0540] As used herein, the term "antiandrogen" refers to any substance capable of inhibiting the biological effects of androgens and includes, but is not limited to, bicalutamide (Casodex). TM The term "gonadotropin-releasing hormone agonist" as used herein includes, but is not limited to, abarelix, goserelin, and goserelin acetate. Goserelin is marketed under the trade name Zoladex. TM Sale.

[0541] The term "topoisomerase I inhibitors" as used herein includes, but is not limited to, topotecan, gimatidecan, irinotecan, camptothecin and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148. Irinotecan can be administered, for example, in the form as it is marketed, for example, under the trademark Camptosar. TM Topotecan is marketed under the trade name HycamptinTM Sale.

[0542] As used herein, the term "topoisomerase II inhibitors" include, but are not limited to, anthracyclines such as doxorubicin (including liposomal formulations such as Caelyx TM ), daunorubicin, epirubicin, idarubicin and nemorubicin, the anthraquinones mitoxantrone and losoxantrone, and the podophyllotoxins etoposide and teniposide. Etoposide is sold under the trade name VanBifur TM Teniposide is sold under the trade name VM 26-Bristol. Doxorubicin is sold under the trade name Acriblastin TM or doxorubicin TM Epirubicin is sold under the trade name Farmorubicin TM Idabixin is sold under the trade name Zavedos TM Mitoxantrone is sold under the trade name Novantron.

[0543] The term "microtubule active agent" refers to microtubule stabilizing compounds, microtubule destabilizing compounds and microtubule polymerization inhibitors, 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; discodermolides; colchicine and epothilones and their derivatives. Paclitaxel is commercially available under the name Taxol. TM Docetaxel is sold under the trade name Taxotere TM Vinblastine sulfate is sold under the trade name Vinblastin RP TM Vincristine sulfate is sold under the trade name Farmistin TM Sale.

[0544] As used herein, the term "alkylating agent" includes, but is not limited to, cyclophosphamide, ifosfamide, melphalan, or nitrosoureas (BCNU or carmustine gliadel). Cyclophosphamide is commercially available under the name Cyclostin TM Ifosfamide is sold under the trade names of Lexan and TM Sale.

[0545] The term "histone deacetylase inhibitor" or "HDAC inhibitor" relates to compounds that inhibit histone deacetylase and have antiproliferative activity. This includes, but is not limited to, suberoylanilide hydroxamic acid (SAHA).

[0546] The term "antineoplastic antimetabolites" includes, but is not limited to: 5-fluorouracil 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 sold under the trade name Xeloda TM Gemcitabine is sold under the trade name Gemcitabine TM Sale.

[0547] The term "platinum compound" as used herein includes, but is not limited to, carboplatin, cis-platin, cisplatinum and oxaliplatin. Carboplatin can be administered, for example, in the form in which it is sold, for example, under the trademark Carboplat TM Oxaliplatin can be administered, eg, in the form as it is marketed, eg under the trademark Eloxatin TM Down.

[0548] As used herein, the term "compounds that target / decrease the activity of a protein or lipid kinase, or a protein or lipid phosphatase; or another anti-angiogenic compound" includes, but is not limited to, protein tyrosine kinase and / or serine and / or threonine kinase inhibitors or lipid kinase inhibitors, such as a) compounds that target, decrease or inhibit the activity of platelet-derived growth factor-receptor (PDGFR), such as compounds that target, decrease or inhibit the activity of PDGFR, in particular compounds that inhibit the PDGF receptor, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib, SUGAMIN, LASIK ... 101, SU6668 and GFB-111; b) compounds that target, reduce or inhibit the activity of fibroblast growth factor-receptor (FGFR); c) compounds that target, reduce or inhibit the activity of insulin-like growth factor receptor I (IGF-IR), such as compounds that target, reduce or inhibit the activity of IGF-IR, especially compounds that inhibit the kinase activity of IGF-I receptor, or antibodies that target the extracellular domain of IGF-I receptor or its growth factor; d) compounds that target, reduce or inhibit the activity of Trk receptor tyrosine kinase family or ephrin B4 inhibitors; e) compounds that target, decrease or inhibit the activity of the AxI receptor tyrosine kinase family; f) compounds that target, decrease or inhibit the activity of the Ret receptor tyrosine kinase; g) compounds that target, decrease or inhibit the activity of the Kit / SCFR receptor tyrosine kinase, such as imatinib; h) compounds that target, decrease or inhibit the activity of the c-kit receptor tyrosine kinase, which is part of the PDGFR family, such as compounds that target, decrease or inhibit the activity of the c-Kit receptor tyrosine kinase family, in particular compounds that inhibit the c-Kit receptor, such as imatinib; i) compounds that target, decrease or inhibit the activity of c-Abl family members, their gene fusion products (e.g., BCR-Abl kinase) and mutants, such as compounds that target, decrease or inhibit c-Abl family members and their gene fusion products, such as N-phenyl-2-pyrimidinyl-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC 680410; PD173955 from Parke Davis; or dasatinib (BMS-354825); j) compounds that target, decrease or inhibit the activity of members of the protein kinase C (PKC) and Raf families of serine / threonine kinases; members of the MEK, SRC, JAK / pan-JAK, FAK, PDK1, PKB / Akt, Ras / MAPK, PI3K, SYK, TYK2, BTK and TEC families; and / or members of the cyclin-dependent kinase family (CDK), including staurosporine derivatives, such as midostaurin;Examples of additional compounds include UCN-01, safingol, BAY 43-9006, Bryostatin 1, Perifosine; Imofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531 / LY379196; Isoquinoline compounds; FTIs; PD184352 or QAN697 (a P13K inhibitor) or AT7519 (a CDK inhibitor); k) compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors, such as compounds that target, decrease or inhibit the activity of protein tyrosine kinase inhibitors include imatinib mesylate (Gleevec; TM ) or tyrosine phosphoinhibitors such as tyrosine phosphoinhibitor A23 / RG-50810; AG 99; tyrosine phosphoinhibitor AG 213; tyrosine phosphoinhibitor AG 1748; tyrosine phosphoinhibitor AG 490; tyrosine phosphoinhibitor B44; tyrosine phosphoinhibitor B44(+) enantiomer; tyrosine phosphoinhibitor AG 555; AG 494; tyrosine phosphoinhibitor AG 556, AG957 and adaphostin (4-{[(2,5-dihydroxyphenyl)methyl]amino}-benzoic acid adamantyl ester; NSC 680410, adaphostin); l) compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR1ErbB2, 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, especially compounds, proteins or antibodies that inhibit EGF receptor tyrosine kinase family members such as EGF receptor, ErbB2, ErbB3 and ErbB4 or bind to EGF or EGF-related ligands CP 358774, ZD 1839, ZM 105180; trastuzumab (Herceptin TM ), Cetuximab (Erbitux TM), Iressa, Tarceva, OSI-774, Cl-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo-[2,3-d]pyrimidine derivatives; m) compounds that target, decrease or inhibit the activity of c-Met receptor, such as compounds that target, decrease or inhibit the activity of c-Met, especially compounds that inhibit the kinase activity of c-Met receptor, or compounds that target c-Me n) compounds that target, decrease or inhibit the kinase activity of one or more JAK family members (JAK1 / JAK2 / JAK3 / TYK2 and / or pan-JAK), including but not limited to PRT-062070, SB-1578, baricitinib, pacritinib, momelotinib, VX-509, AZD-1480, TG-10 o) compounds that target, decrease 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, datonisib, (dactolisib), XL-147, XL-765 and idelalisib; and; and q) compounds that target, decrease or inhibit signaling of the hedgehog (Hh) or smoothened receptor (SMO) pathways, including, but not limited to, cyclopamine, vismodegib, itraconazole, erismodegib and IPI-926 (saridegib).

[0549] As used herein, the term "PI3K inhibitor" 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, PI3Kα, PI3Kγ, PI3Kδ, PI3Kβ, PI3K-C2α, PI3K-C2β, PI3K-C2γ, Vps34, p110-α, p110-β, p110-γ, p110-δ, p85-α, p85-β, p55-γ, p150, p101, and p87. Examples of PI3K inhibitors that can be used in the present invention include, but are not limited to, ATU-027, SF-1126, DS-7423, PBI-05204, GSK-2126458, ZSTK-474, bupanib, picotensib, PF-4691502, BYL-719, daltonisib, XL-147, XL-765, and idelalisib.

[0550] As used herein, the term "Bcl-2 inhibitor" includes, but is not limited to, compounds that have inhibitory activity against B-cell lymphoma 2 protein (Bcl-2), including, but not limited to, ABT-199, ABT-731, ABT-737, apogossypol, Ascenta's pan-Bcl-2 inhibitor, curcumin (and its analogs), dual Bcl-2 / Bcl-xL inhibitors (Infinity Pharmaceuticals / Novartis Pharmaceuticals), Genasense (G3139), HA14-1 (and its analogs; see WO2008118802), navitoclax (and its analogs, see US7390799), NH-1 (Shenayng Pharmaceutical University), obaclax (and its analogs, see WO2004106328), S-001 (Gloria Pharmaceuticals), TW series compounds (Univ. of Michigan), and venetoclax. In certain embodiments, the Bcl-2 inhibitor is a small molecule therapeutic agent. In certain embodiments, the Bcl-2 inhibitor is a peptidomimetic.

[0551] As used herein, the term "BTK inhibitor" 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.

[0552] As used herein, the term "SYK inhibitor" 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.

[0553] Further examples of BTK inhibitory compounds and conditions treatable by combination of such compounds with the compounds of the present invention can be found in WO2008039218 and WO2011090760, the entire contents of which are incorporated herein by reference.

[0554] Further examples of SYK inhibitory compounds and conditions treatable by combination of such compounds with the compounds of the invention can be found in WO2003063794, WO2005007623 and WO2006078846, the entire contents of which are incorporated herein by reference.

[0555] Other examples of PI3K inhibitory compounds and conditions treatable by combination of such compounds with the compounds of the present invention can be found in WO2004019973, WO2004089925, WO2007016176, US8138347, WO2002088112, WO2007084786, WO2007129161, WO2006122806, WO2005113554 and WO2007044729, the entire contents of which are incorporated herein by reference.

[0556] Further examples of JAK inhibitory compounds and conditions treatable by combination of such compounds with the compounds of the invention can be found in WO2009114512, WO2008109943, WO2007053452, WO2000142246 and WO2007070514, the entire contents of which are incorporated herein by reference.

[0557] Additional anti-angiogenic compounds include compounds that have another mechanism for their activity, for example, unrelated to protein or lipid kinase inhibition, such as thalidomide. TM ) and TNP-470.

[0558] Examples of proteasome inhibitors that can be used in combination with the compounds of the present invention include, but are not limited to, bortezomib, disulfiram, epigallocatechin-3-gallate (EGCG), salinosporamide A, carfilzomib, ONX-0912, CEP-18770, and MLN9708.

[0559] Compounds which target, decrease 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.

[0560] Compounds that induce cell differentiation processes include, but are not limited to, retinoic acid, α-γ- or δ-tocopherol, or α-γ- or δ-tocotrienol.

[0561] The term cyclooxygenase inhibitors as used herein includes, but is not limited to, Cox-2 inhibitors, 5-alkyl substituted 2-arylaminophenylacetic acids and derivatives such as celecoxib (Celebrex), TM ), rofecoxib (Vioxx TM ), etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid such as 5-methyl-2-(2'-chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib.

[0562] As used herein, the term "bisphosphonates" includes, but is not limited to, etridonic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid, and zoledronic acid. TM Clodronic acid is sold under the trade name Gufushu TM (Bonefos TM ). Tiludronic acid is sold under the trade name Skelid TM Pamidronate is sold under the trade name Acorda TM (Aredia TM ). Alendronate is sold under the trade name Fosamax TM Ibandronic acid is sold under the trade name Bondranat TM Risedronate is sold under the trade name Actonel TM Zoledronic acid is sold under the trade name Zometa TM (Zometa TM The term "mTOR inhibitor" refers to compounds that inhibit the mammalian target of rapamycin (mTOR) and have antiproliferative activity, such as sirolimus Everolimus (Certican TM ), CCI-779 and ABT578.

[0563] As used herein, the term "heparanase inhibitor" refers to a compound that targets, reduces, or inhibits the degradation of heparan sulfate. This term includes, but is not limited to, PI-88. As used herein, the term "biological response modifier" refers to a lymphokine or interferon.

[0564] As used herein, the term "inhibitor of an oncogenic isoform of Ras," such as H-Ras, K-Ras, or N-Ras, refers to a compound that targets, decreases, or inhibits the oncogenic activity of Ras; for example, a "farnesyltransferase inhibitor," such as L-744832, DK8G557, or R115777 (Zarnestra TM As used herein, the term "telomerase inhibitor" refers to a compound that targets, reduces, or inhibits the activity of telomerase. Compounds that target, reduce, or inhibit telomerase activity are particularly compounds that inhibit the telomerase receptor, such as telomestatin.

[0565] The term "methionine aminopeptidase inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of methionine aminopeptidase. Compounds that target, reduce or inhibit the activity of methionine aminopeptidase include, but are not limited to, bengamide or its derivatives.

[0566] The term "proteasome inhibitor" as used herein refers to a compound that targets, reduces or inhibits the activity of the proteasome. Compounds that target, reduce or inhibit the activity of the proteasome include, but are not limited to, bortezomib (Velcade TM ) and MLN341.

[0567] As used herein, the term "matrix metalloproteinase inhibitors" or ("MMP" inhibitors) include, but are not limited to, collagen peptidomimetics and non-peptide mimetic inhibitors, tetracycline derivatives, such as the hydroxamic acid peptidomimetic inhibitor batimastat and its orally bioavailable analogs marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551), BMS-279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

[0568] As used herein, the term "compounds for the treatment of hematological malignancies" includes, but is not limited to: FMS-like tyrosine kinase inhibitors, which are compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R); interferons, 1-β-D-arabinofuranosylcytosine (arabinoside) and bisulfan; and ALK inhibitors, which are compounds that target, decrease or inhibit anaplastic lymphoma kinase.

[0569] Compounds that target, decrease or inhibit the activity of the FMS-like tyrosine kinase receptor (Flt-3R) are, in particular, compounds, proteins or antibodies that inhibit members of the Flt-3R receptor kinase family, such as PKC412, midostaurin, staurosporine derivatives, SU11248 and MLN518.

[0570] As used herein, the term "HSP90 inhibitor" includes, but is not limited to, compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90; compounds that degrade, target, reduce, or inhibit HSP90 client proteins via the ubiquitin proteasome pathway. Compounds that target, reduce, or inhibit the intrinsic ATPase activity of HSP90, in particular, compounds, proteins, or antibodies that inhibit the ATPase activity of HSP90, such as 17-allylamino, 17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin-related compounds; radicicol; and HDAC inhibitors.

[0571] The term "anti-proliferative antibodies" as used herein include, but are not limited to: trastuzumab (Herceptin TM ), trastuzumab-DM1, erbitux, bevacizumab (atorvastatin TM ), rituximab PRO64553 (anti-CD40) and 2C4 antibodies. Antibodies refer to intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least two intact antibodies, and antibody fragments, as long as they exhibit the desired biological activity.

[0572] For the treatment of acute myeloid leukemia (AML), the compounds of the present invention can be used in combination with standard leukemia therapies, in particular, in combination with therapies for the treatment of AML. Specifically, the compounds of the present invention can be administered in combination with, for example, the following agents: farnesyl transferase inhibitors and / or other drugs that can be used to treat AML, such as daunorubicin, doxorubicin, cytarabine, VP-16, teniposide, mitoxantrone, idarubicin, carboplatinum, and PKC412.

[0573] Other anti-leukemia compounds include, for example, cytarabine, a pyrimidine analog that is a 2'-α-hydroxyribose (cytarabine) derivative of deoxycytidine. Also included are purine analogs 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 an enzyme called histone deacetylase. 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-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, and N-hydroxy-3-[4-[(2-hydroxyethyl){2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2-acrylamide or a pharmaceutically acceptable salt thereof, especially lactate. As used herein, somatostatin receptor antagonists refer to compounds that target, treat or inhibit somatostatin receptors, such as octreotide and SOM230. Tumor cell damage methods refer to methods such as ionizing radiation. As used herein and hereinbelow, the term "ionizing radiation" refers to ionizing radiation produced as 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, Principles and Practice of Oncology, Devita et al., eds., 4th ed., Vol. 1, pp. 248-275 (1993).

[0574] Also included are EDG binders and ribonucleotide reductase inhibitors. The term "EDG binder" as used herein refers to a class of immunosuppressants that regulate lymphocyte recirculation, such as FTY720. The term "ribonucleotide reductase inhibitor" refers to pyrimidine or purine nucleoside analogs, including but not limited to fludarabine and / or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-mercaptopurine (particularly for ALL in combination with arabinoside) and / or pentostatin. Ribonucleotide reductase inhibitors are particularly hydroxyurea or 2-hydroxy-1H-isoindole-1,3-dione derivatives.

[0575] Also specifically included are those compounds, proteins or monoclonal antibodies to VEGF, such as 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine succinate; Angiostatin TM ;Endostatin TM ; anthranilamide; ZD4190; Zd6474; SU5416; SU6668; bevacizumab; or anti-VEGF antibodies or anti-VEGF receptor antibodies, such as rhuMAb and RHUFab, VEGF aptamers such as Macugon; FLT-4 inhibitors, FLT-3 inhibitors, VEGFR-2 IgGI antibodies, Angiozyme (RPI 4610) and bevacizumab (atorvastatin TM ).

[0576] As used herein, photodynamic therapy refers to therapy that uses certain chemicals called photosensitizing compounds to treat or prevent cancer. Examples of photodynamic therapy include the use of compounds such as Visudyne TM and porfimer sodium treatment.

[0577] As used herein, angiogenesis-inhibiting steroids refer to compounds that block or inhibit angiogenesis, for example, anecortave, triamcinolone, hydrocortisone, 11-α-epihydrocotisol, cortexolone, 17α-hydroxyprogesterone, corticosterone, deoxycorticosterone, testosterone, estrone, and dexamethasone.

[0578] Implants containing corticosteroids refer to compounds such as fluocinolone and dexamethasone.

[0579] Other chemotherapeutic compounds include, but are not limited to: plant alkaloids, hormone compounds and antagonists; biological response modifiers, preferably lymphokines or interferons; antisense oligonucleotides or oligonucleotide derivatives; shRNA or siRNA; or other compounds or compounds with other or unknown mechanisms of action.

[0580] The structures of active compounds identified by code names, generic names or trade names can be taken from actual editions of the standard compendium "The Merck Index" or from databases such as Patents International (eg IMS World Publications).

[0581] The compounds of the present invention may also be used in combination with known treatment methods such as administration of hormones or radiation.In certain embodiments, provided compounds are useful as radiosensitizers, particularly for treating tumors that exhibit poor sensitivity to radiation therapy.

[0582] The compounds of the present invention can be administered alone or in combination with one or more other therapeutic compounds, with possible combination therapies taking the form of fixed combinations, or the administration of the compounds of the present invention and one or more other therapeutic compounds being staggered or performed independently of one another, or the combination of fixed combinations and one or more other therapeutic compounds. In addition or in addition, the compounds of the present invention can be administered specifically for tumor treatment in combination with chemotherapy, radiotherapy, immunotherapy, phototherapy, surgical intervention, or a combination of these. Long-term therapy is also possible, as is adjuvant therapy in the context of other treatment strategies as described above. Other possible treatments are therapies that maintain the patient's status after tumor regression, or even chemopreventive therapy, for example, in patients at risk.

[0583] Those additional agents may be administered separately from the composition containing the compounds of the invention as part of a multiple-dose regimen. Alternatively, those agents may be part of a single dosage form mixed with the compounds of the invention in a single composition. If administered as part of a multiple-dose regimen, the two active agents may be delivered simultaneously, sequentially, or within a period of time (usually within five hours of each other).

[0584] As used herein, the terms "combination," "combined," and related terms refer to the simultaneous or sequential administration of therapeutic agents according to the present invention. For example, a compound of the present invention can be administered simultaneously or sequentially with another therapeutic agent (in separate unit dosage forms or together in a single unit dosage form). Thus, 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.

[0585] The amount of the compound of the invention and the additional therapeutic agent (in those compositions comprising additional therapeutic agents as described above) that can be combined with the carrier materials to produce a single dosage form will vary depending on the host being treated and the particular mode of administration. Preferably, the compositions of the invention should be formulated so that a dosage of 0.01-100 mg / kg body weight / day of the compound of the invention can be administered.

[0586] In those compositions comprising an additional therapeutic agent, the additional therapeutic agent and the compounds of the invention may act synergistically. Thus, the amount of the additional therapeutic agent in such a composition will be less than the amount required in a monotherapy utilizing only that therapeutic agent. In such a composition, a dosage of 0.01-1,000 μg / kg body weight / day of the additional therapeutic agent may be administered.

[0587] The amount of additional therapeutic agent present in the compositions of the present invention will not exceed the amount normally 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 ranges from about 50% to 100% of the amount normally present in a composition comprising that agent as the only therapeutically active agent.

[0588] The compounds of the present invention or their pharmaceutical compositions can also be incorporated into compositions for coating implantable medical devices such as prostheses, artificial valves, vascular grafts, stents, and catheters. For example, vascular stents have been used to overcome restenosis (restenosis of the blood vessel wall after injury). However, patients using stents or other implantable devices may be at risk of developing clots or 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 the compounds of the present invention are another embodiment of the present invention.

[0589] illustration

[0590] General synthetic methods

[0591] The following examples are intended to illustrate the present invention and should not be construed as limiting it. Unless otherwise stated, one or more tautomeric forms of the compounds of the embodiments described hereinafter can be prepared and / or separated in situ. All tautomeric forms of the compounds of the embodiments described hereinafter should be considered to be disclosed. Temperature is given in degrees Celsius. If not otherwise mentioned, all evaporations are performed under reduced pressure, preferably between about 15mm Hg to 100mm Hg (=20-133 millibars). The structures of the final products, intermediates and starting materials are confirmed by standard analytical methods, for example, microanalysis and spectral characteristics, for example, MS, IR, NMR. The abbreviations used are conventional abbreviations in this area.

[0592] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts for synthesizing the compounds of the present invention are commercially available, or can be produced by organic synthesis methods known to those of ordinary skill in the art (Houben-Weyl 4th edition 1952, Methods of Organic Synthesis, Thieme, Vol. 21). In addition, compounds of the present invention can be produced by organic synthesis methods known to those of ordinary skill in the art as shown in the following examples.

[0593] abbreviation

[0594] equiv or eq: molar equivalent

[0595] o / n: Overnight

[0596] rt: room temperature

[0597] UV: Ultraviolet

[0598] HPLC: High-pressure liquid chromatography

[0599] Rt: retention time

[0600] LCMS or LC-MS: Liquid Chromatography-Mass Spectrometry

[0601] NMR: Nuclear Magnetic Resonance

[0602] CC: Column chromatography

[0603] TLC: Thin layer chromatography

[0604] sat: saturated

[0605] aq: water-based

[0606] Ac: Acetyl

[0607] DCM: dichloromethane

[0608] DCE: dichloroethane

[0609] DEA: Diethylamine

[0610] DMF:Dimethylformamide

[0611] DMSO: dimethyl sulfoxide

[0612] ACN or MeCN: acetonitrile

[0613] DIPEA:Diisopropylethylamine

[0614] EA or EtOAc: ethyl acetate

[0615] BINAP:(±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

[0616] TEA:Triethylamine

[0617] THF:Tetrahydrofuran

[0618] TBS: tert-butyldimethylsilyl

[0619] KHMDS: Potassium hexamethyldisilyl azide

[0620] Tf:Trifluoromethanesulfonate

[0621] Ms:Methylsulfonyl

[0622] NBS:N-bromosuccinimide

[0623] PE:Petroleum ether

[0624] TFA: trifluoroacetic acid

[0625] FA: Formic acid

[0626] MMPP:Magnesium monoperoxyphthalate

[0627] HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridine 3-oxide hexafluorophosphate

[0628] Cy: Cyclohexyl

[0629] Tol:Toluene

[0630] DMP: Dess-Martin periodinane

[0631] IBX:2-Iodoacylbenzoic acid

[0632] PMB: p-methoxybenzyl

[0633] SEM: [2-(Trimethylsilyl)ethoxy]methyl

[0634] XPhos or X-Phos: 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl

[0635] General Information: All evaporations were performed in vacuo using a rotary evaporator. Analytical samples were dried in vacuo (1-5 mmHg) at room temperature. Thin layer chromatography (TLC) was performed on silica gel plates and spots were visualized by 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 mixtures by volume. All reactions were recorded on a Bruker 400 (400 MHz) spectrometer. 1 H NMR spectra. Deuterated solvents were used as internal standards and δ values ​​were reported in parts per million (ppm). 1 H chemical shift. Data are reported as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, 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 using electrospray ionization, and unless otherwise indicated, general LCMS conditions were as follows: Waters X Bridge C18 column (50 mm * 4.6 mm * 3.5 μm), flow rate: 2.0 mL / min, column temperature: 40°C.

[0636] Example 1

[0637] Synthesis Scheme 1: (R)-N-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenyl)acetamide (6) I-10 and (S)-N-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenyl)acetamide (7) I-15

[0638]

[0639] (a) 4A molecular sieves, 2-chloro-5-nitrobenzaldehyde, CH2Cl2; (b) 2,6-lutidine, Cu(OTf)2, hexafluoroisopropanol, CH2Cl2; c) Boc2O, Et3N, THF; (d) zinc, NH4Cl, 2% TPGS-750-M in water, 75°C; (e) AcCl, Et3N, CH2Cl2; (f) TFA, CH2Cl2; (g) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (h) SFC chiral separation

[0640] Formation of (±)-3-(2-chloro-5-nitrophenyl)-1,4-oxazepane (1)

[0641] To a solution of 3-(tributylstannylmethoxy)propan-1-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 at room temperature overnight, filtered to remove the molecular sieves, and diluted with dichloromethane (75 mL). In a separate flask containing hexafluoroisopropanol (22 mL), 2,6-lutidine (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, after which the imine solution prepared above was added in one portion. The reaction was stirred at room temperature overnight. The mixture was diluted with 150 mL of a 2:1 saturated aqueous NaHCO₃ solution and 10% ammonium hydroxide. After stirring for 20 minutes, the organic layer was removed and washed with a saturated aqueous NaHCO₃ solution, followed by brine. The organic layer was passed through a phase separation funnel and concentrated in vacuo. Purification by reverse phase silica gel chromatography using an ISCO-100 gram c18-aq column (eluted with 0.2% formic acid / H2O and 0.2% formic acid / CH3CN) gave 700 mg of the desired product as an orange-red residue which was used without further purification: 1H NMR (d6-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, 8.5 Hz, 1H), 3.18-2.86 (m, 2H), 1.95-1.84 (m, 2H); ESI-MS m / z calculated 256.06146, found 257.13 (M+1) + ; Retention time: 0.52 minutes.

[0642] Formation of tert-butyl (±)-3-(2-chloro-5-nitrophenyl)-1,4-oxazepane-4-carboxylate (2)

[0643] A mixture of 3-(2-chloro-5-nitro-phenyl)-1,4-oxazepane (0.50 g, 1.93 mmol) and triethylamine (0.27 mL, 1.94 mmol) in THF (7 mL) was added to di-tert-butyl dicarbonate (0.42 g, 1.93 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted into a saturated aqueous NH4Cl solution and extracted with dichloromethane. The organic phase was passed through a phase separation funnel and concentrated in vacuo. The crude residue was purified by silica gel chromatography using a 40 g ISCO Gold column (0-20% EtOAc / CH2Cl2 gradient) to give 376 mg of the desired product as an off-white solid: ESI-MS m / z calculated 356.1139, found 356.82 (M+1) + ; Retention time: 0.92 minutes.

[0644] Formation of tert-butyl 3-(5-amino-2-chlorophenyl)-1,4-oxazepane-4-carboxylate (3)

[0645] A suspension of tert-butyl 3-(2-chloro-5-nitro-phenyl)-1,4-oxazepane-4-carboxylate (1.98 g, 5.55 mmol), NH4Cl (1.20 g, 22.43 mmol) and zinc (2.00 g, 30.58 mmol) was stirred in a 2% aqueous solution of TPGS-750-M (50 mL). The reaction mixture was stirred vigorously and heated to 75°C for 23 hours. The mixture was diluted into a saturated aqueous solution of NaHCO3 and extracted with dichloromethane. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using 10-50% (20% MeOH-CH2Cl2 / CH2Cl2 gradient) with an 80 g isco column to give 2 g of the desired product as a light yellow solid which was used without further purification; ESI-MS m / z calcd 356.1139, found 227.14 (M-Boc) + ; Retention time: 0.64 minutes.

[0646] Formation of tert-butyl (±)-3-(5-acetylamino-2-chlorophenyl)-1,4-oxazepane-4-carboxylate (4)

[0647] To a solution of tert-butyl 3-(5-amino-2-chloro-phenyl)-1,4-oxazepane-4-carboxylate, 3, (0.25 g, 0.69 mmol) and triethylamine (0.15 mL, 1.04 mmol) in dichloromethane (3 mL) was added dropwise a solution of acetyl chloride (0.05 mL, 0.75 mmol) in dichloromethane (1 mL). The reaction mixture was stirred at room temperature for 1 hour. The mixture was quenched by the addition of saturated aqueous NaHCO3 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 using a 0-30% (20% MeOH-CH2Cl2 / CH2Cl2) gradient with a 40g iscoGOLD column to give 185 mg of a white solid, which was cleaned by LCMS. ESI-MS m / z calculated 368.15, found 369.42 (M+1) + ; Retention time: 0.8 minutes.

[0648] Formation of (±)-N-(4-chloro-3-(1,4-oxazepan-3-yl)phenyl)acetamide (5)

[0649] To a solution of tert-butyl 3-(5-acetylamino-2-chloro-phenyl)-1,4-oxazepane-4-carboxylate, 4, (0.18 g, 0.47 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (1.5 mL). 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 NaHCO3 aqueous solution. The organic phase was passed through a phase separator, and the resulting filtrate was concentrated in vacuo to give 70 mg of the product as a white solid, which was used without further purification: ESI-MS m / z calculated 268.09, found 269.20 (M+1) + ; Retention time: 0.5 minutes; 1 HNMR (400MHz, DMSO-d6) δ10.04(s,1H),7.72(d,J=2.6Hz,1H),7.64(dd,J=8.7,2.7Hz,1H),7.29(d,J=8.7Hz,1H),4.18(dd,J=9.2,3.1Hz,1H),3.90-3.7 3(m,2H),3.67(dt,J=11.9,6.5Hz,1H),3.20(dd,J=12.2,9.1Hz,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).

[0650] Formation of the (R)-isomer (6) and (S)-isomer (7) of N-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenyl)acetamide

[0651] To a solution of N-[4-chloro-3-(1,4-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 to 150° C. for 18 hours. The mixture was cooled to room temperature and directly loaded onto a 50 g ISCO c18-aq column and purified on a reverse phase with 0.1% TFA / H2O and 0.1% TFA / CH3CN. The pure fractions were concentrated in vacuo. The residue was diluted with dichloromethane and neutralized with saturated aqueous NaHCO3. The organic phase was passed through a phase separator and concentrated in vacuo to give 69 mg of a light orange solid: high temperature (360 K) 1H NMR (d6-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 calculated 375.15, found 376.31 (M+1) + Retention time: 0.56 min. The racemic mixture was purified by chiral SFC to afford the individual enantiomers.

[0652] Peak A (R)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]acetamide: high temperature (360K) 1 H NMR(400MHz, DMSO-d6)δ9.70(s,1H),7.56(dd,J=8.6,2.6Hz,1H),7.50(d,J=2.6Hz,1H ),7.31(d,J=8.7Hz,1H,5.55(s,1H),5.44(s,2H),5.34(s,1H),4.67(d,J=15.1Hz,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); ESI-MS m / z calculated 375.14, found 376.27 (M+1) + ; Retention time: 0.56 minutes.

[0653] Peak B (S)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]acetamide: high temperature (360K) 1H NMR(400MHz, DMSO-d6)δ9.71(s,1H),7.56(dd,J=8.6,2.6Hz,1H),7.50(d,J=2.6Hz,1H ),7.31(d,J=8.7Hz,1H,5.55(s,1H),5.44(s,2H),5.34(s,1H),4.67(d,J=15.1Hz,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); ESI-MS m / z calculated 375.14, found 376.27 (M+1) + ; Retention time: 0.56 minutes. [α] D =+41.2°.

[0654] The following analogs were prepared according to Synthetic Scheme 1:

[0655]

[0656] (±)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)acetamide I-141

[0657] High temperature (360K) 1 H NMR (400 MHz, DMSO-d6) 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), 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 calculated 375.15, found 376.27 (M+1) + ; Retention time: 0.55 minutes.

[0658] SFC chiral separation of racemic material.

[0659] Peak A: (R)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)acetamide (8) [α] D= -19.49 (c = 4.1 mg / 0.8 mL MeOH); high temperature (360 K) 1 H NMR (400 MHz, DMSO-d6) 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); ESI-MS m / z calculated 375.15, found 376.31 (M+1) + ; Retention time: 0.55 minutes. I-310

[0660] Peak B: (S)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)acetamide (9) [α] D = +13.75 (c = 4.3 mg / 0.8 mL MeOH); high temperature (360 K) 1 H NMR (400 MHz, DMSO-d6) 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); ESI-MS m / z calculated 375.15, found 376.31 (M+1) + ; Retention time: 0.55 minutes. I-162

[0661]

[0662] (S)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)propanamide (10) I-204

[0663] Peak B from SFC chiral separation: 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 calculated 389.2, found 390.4 (M+1) + ; Retention time: 0.58 minutes.

[0664]

[0665] (S)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)propanamide (11) I-207

[0666] Peak B from SFC chiral separation: 99.8% ee; heating (360K) 1 H NMR(400MHz,d6-DMSO)δ10.03(s,1H),7.80(d,J=2.0Hz,1H),7.37(dd,J=8.5,2.1Hz ,1H),7.21(d,J=8.5Hz,1H),5.56(s,1H),5.46(s,2H),5.33(s,1H),4.63(d,J=14.1H z, 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 calculated 401.2, found 402.3 (M+1) + ; Retention time: 0.59 minutes.

[0667]

[0668] (±)-N-[4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-3-chloro-phenyl]-2-methoxy-acetamide (12) I-192

[0669] Heating (360K) 1H NMR (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 calcd 405.2, found 406.3 (M+1) + ; Retention time: 0.56 minutes.

[0670]

[0671] (S)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)propanamide (13) I-197

[0672] Peak B from SFC chiral separation: 99.4% ee; 1 H NMR (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 = 7.7, 4.5 Hz, 2H); ESI-MS m / z calcd 417.2, found 418.3 (M+1) + ; Retention time: 0.56 minutes.

[0673]

[0674] (±)-N-[5-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-2-fluoro-phenyl]acetamide (14) I-85

[0675] 1H NMR (300 MHz, CDCl3) 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 calculated 393.1, found 394.1 (M+1) + ; Retention time: 0.59 minutes.

[0676] SFC chiral separation of racemic material. Conditions: 20x250mm IC column, mobile phase: 40% MeOH (5mM ammonia), 60% CO2

[0677] Peak A: N-[5-[(3R)-4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-2-fluoro-phenyl]acetamide (15): 1 H NMR (300 MHz, methanol-d4) 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 calculated 393.1, found 394.1 (M+1) + Retention time: 0.59 minutes; Optical rotation: 5 mg / 1 mL MeOH, C = 1, [α] = -62.24°. I-270

[0678] Peak B: N-[5-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-2-fluoro-phenyl]acetamide (16): 1H NMR (300 MHz, methanol-d4) 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 calculated 393.1, found 394.2 (M+1) + Optical rotation: 5 mg / 1 mL MeOH, C = 1, [α] = 59.6°. I-271

[0679]

[0680] (±)-4-[3-[2-chloro-5-(ethylamino)-4-fluoro-phenyl]-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (17) I-272

[0681] To a solution of N-[5-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-2-fluoro-phenyl]acetamide, 14, (0.05 g, 0.12 mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride (0.08 mL 2M, 0.16 mmol) in THF. The turbid solution was stirred at room temperature overnight. Additional lithium aluminum hydride (0.10 mL) was added and the reaction mixture was heated to 60° C. overnight. The mixture was diluted with water (0.25 mL) and stirred for 10 minutes. Dichloromethane (10 mL) was added 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 4 g ISCO column eluted with a 0-10% MeOH / dichloromethane gradient to give the desired product as a white solid: 1 H NMR (300 MHz, chloroform-d) δ 7.02 (d, J = 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 = 7.1, 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 calculated 379.2, found 379.8 (M+1)+ ; Retention time: 0.66 minutes.

[0682] Example 2

[0683] Synthesis Scheme 2: (±)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (19) I-66

[0684]

[0685] (a) 4A molecular sieve, 2-chloro-4-(methylsulfonyl)benzaldehyde, CH2Cl2; (b) 2,6-lutidine, Cu(OTf)2, hexafluoroisopropanol, CH2Cl2; c) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (d) SFC chiral separation

[0686] Formation of (±)-3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepane (18)

[0687] To a solution of 3-(tributylstannylmethoxy)propane-1-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 molecular sieves and washed and diluted with dichloromethane (50 mL).

[0688] 2,6-lutidine (0.53mL, 4.58mmol) was added to a separate flask containing hexafluoroisopropanol (15mL), followed by Cu(OTf)2 (1.65g, 4.56mmol). The mixture was stirred for 1h, and then the imine solution prepared above was added in a single batch. The reactants were stirred at room temperature overnight. The mixture was diluted with a 2:1 mixture of saturated NaHCO3 aqueous solution and 10% ammonium hydroxide. After stirring for 10 minutes, the organic layer was removed and washed with a saturated NaHCO3 aqueous solution, followed by a brine wash. The organic layer was passed through a phase separation funnel and the filtrate was concentrated in vacuo. The residue was purified by reverse phase chromatography using an ISCO-100 gram c18-aq column (eluted with formic acid / H2O and formic acid / CH3CN gradient). The residue was diluted with dichloromethane and neutralized with a saturated NaHCO3 aqueous solution. The organic phase was passed through a phase separator and concentrated in vacuo to obtain 688mg of the desired product: 1H NMR (400 MHz, DMSO-d6) 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 calculated 289.05396, found 290.05 (M+1) + ; Retention time: 0.5 minutes

[0689] Formation of (R)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (20) I-67 and (S)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (21) I-68

[0690] To a solution of 3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepane, 18, (0.67 g, 2.31 mmol) in NMP (7.5 mL) was added 4-chloro-6-methyl-pyrimidin-2-amine (0.40 g, 2.79 mmol). The reaction mixture was heated to 150 ° C and kept overnight. The mixture was cooled to room temperature and directly loaded onto a 100g ISCO c18-aq column and reverse-phase purified with 0.1% TFA / H2O and 0.1% TFA / CH3CN. The pure fractions were concentrated in vacuo. The obtained residue was diluted with dichloromethane and neutralized with saturated NaHCO3 aqueous solution. The mixture was passed through a phase separator and the organic phase was concentrated in vacuo to obtain 550 mg of the desired product. The racemic mixture was subjected to SFC chiral purification to obtain 155 mg of stereoisomer A and 153 mg of stereoisomer B:

[0691] Peak A: (R)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (20), heated 1H NMR(360K)(400MHz,DMSO-d6)δ7.97(t,J=1.9Hz,1H),7.84(dt,J=8.2,1.9Hz,1 H),7.60(dd,J=8.1,2.0Hz,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),1.89-1.70(m,2H); ESI-MS m / z calculated 396.10, found 397.16 (M+1) + ; Retention time: 0.57 min; [□] D = -71.67 (c = 5.4 mg / 1.5 mL MeOH). I-67

[0692] Peak B: (S)-4-(3-(2-chloro-4-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (21), heated 1 H NMR(360K)(400MHz,DMSO-d6)δ7.94(d,J=2.0Hz,1H),7.80(dd,J=8.1,2.0Hz,1H) ,7.56(d,J=8.2Hz,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=13.5,4.8Hz,1H),3.97-3.85(m,1H),3.85-3.64(m,2H), 3.57(dt,J=12.4,7.4Hz,1H),3.21(s,3H),2.03(s,3H),1.90-1.70(m,2H); ESI-MS m / z calculated 396.10, found 397.16 (M+1) + ; Retention time: 0.56 min; [□] D = +58.36 (c = 5.3 mg / 1.5 mL MeOH). I-68

[0693] The following analogs are synthesized according to Scheme 2:

[0694]

[0695] (R)-4-(2-(2-fluoro-5-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (22) I-26 and (S)-4-(2-(2-fluoro-5-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (23) I-27

[0696] The racemic mixture was synthesized in the same manner and then subjected to chiral SFC purification to afford the individual enantiomers:

[0697] Peak A; 98.6% ee; high temperature (360K) 1 H NMR(400MHz,DMSO-d6)δ7.10-6.9 4(m,2H),6.84(dd,J=9.5,2.8Hz,1H),5.59(s,1H),5.54-5.29(m,3H),4.70-4.47(m,1H),4.16(dd,J=13.2,5.1Hz,1H),3.9 9-3.77(m,4H),3.72-3.40(m,3H),2.00(s,3H),1.86-1.61(m,2H);[□] D =-34.12 (c=19mg / 3mL MeOH). I-26

[0698] Peak B; 97.4% ee; high temperature (360K) 1 H NMR (400MHz, DMSO-d6) δ7.08-6.93(m,2H),6.84(dd,J=9.4,2.8Hz,1H),5.59(s,1H),5.48(s,2H),5.44-5.31(m,1H),4. [□] D = +40.44 (c = 19 mg / 3 mL MeOH); ESI-MS m / z calculated 333.21, found 333.18 (M+1) + ; Retention time: 0.61 minutes. I-27

[0699]

[0700] 4-(3-(2-chloro-5-nitrophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (24) I-72

[0701] High temperature (360K) 1H NMR (400 MHz, DMSO-d6) 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 calculated 363.11, found 364.16 (M+1) + ; Retention time: 0.61 minutes.

[0702]

[0703] (±)-4-[3-(2-chloro-4-nitro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (25) I-125

[0704] High temperature (360K) 1 H NMR (400MHz, DMSO-d6) δ8.22(d,J=2.3Hz,1H),8.08(dd,J=8.6,2.4Hz,1H),7.58(d,J=8.6 Hz,1H),5.69(s,1H),5.59(dd,J=9.9,4.7Hz,1H),5.41(s,2H),4.46(d,J=15.7Hz,1H),4.1 4 (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 calculated 363.11, found 364.25 (M+1) + ; Retention time: 0.6 minutes.

[0705]

[0706] (±)-4-[3-(6-chloro-1,3-benzodioxol-5-yl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (26) I-113

[0707] Heating (360K) 1H NMR (400 MHz, DMSO-d6) 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 calculated 362.1, found 363.0 (M+1) + ; Retention time: 0.71 minutes.

[0708]

[0709] (±)-4-(3-(2-chloro-6-fluorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (27) I-59

[0710] 1 H NMR (400 MHz, DMSO-d6) (heating at 360 K) 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); ESI-MS m / z calculated 336.12, found 337.0 (M+1) + ; Retention time: 0.7 minutes.

[0711]

[0712] (±)-4-(3-(2-chloro-4-(1H-pyrazol-1-yl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (28) I-133

[0713] 1H NMR (400 MHz, DMSO-d6) (heating at 360 K) 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); ESI-MS m / z calculated 384.15, found 385.0 (M+1) + ; Retention time: 0.72 minutes.

[0714]

[0715] (R)-4-(3-(5-chloro-2-methoxyphenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (29) I-131

[0716] 1 H NMR (400MHz, DMSO-d6) (heating 360K) δ7.29(dd,J=8.8,2.7Hz,1H),7.11(d,J=2.7Hz,1H),7.07(d,J=8.8Hz,1H),6.97(s,2H),5.95(d,J=35.3Hz,1H),5.55(s ,1H),4.55(s,1H),4.17(dd,J=13.4,5.2Hz,1H),3.87(s,4H),3.82-3.68(m, 2H), 3.57 (ddd, J=12.2, 8.3, 5.7Hz, 1H), 2.19 (s, 3H), 1.79 (h, J=3.9Hz, 2H). ESI-MS m / z calculated 348.14, found 349.0 (M+1) + ; Retention time: 0.72 minutes.

[0717] (S)-4-(3-(5-chloro-2-methoxyphenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (30) I-132

[0718] 1H NMR (400MHz, DMSO-d6) (heating 360K) δ7.29 (dd, J=8.8, 2.7Hz, 1H), 7.11 (d, J=2.7H z,1H),7.07(d,J=8.8Hz,1H),6.97(s,2H),5.95(d,J=35.3Hz,1H),5.55(s,1H ),4.55(s,1H),4.17(dd,J=13.4,5.2Hz,1H),3.87(s,4H),3.82-3.68(m,2H), 3.57(ddd,J=12.2,8.3,5.7Hz,1H),2.19(s,3H),1.79(h,J=3.9Hz,2H); ESI-MS m / z calculated 348.14, found 349.0 (M+1) + ; Retention time: 0.72 minutes.

[0719]

[0720] (±)-4-(3-(4-bromo-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (31) I-194

[0721] High temperature (360K) 1 H NMR (400 MHz, DMSO-d6) 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 calculated 396.0, found 397.0 (M+1) + ; Retention time: 0.64 minutes.

[0722] SFC chiral separation of racemic material.

[0723] Peak A: ESI-MS m / z calculated 396.0, found 399.0 (M+1) + Retention time: 0.8 min; (R)-4-(3-(4-bromo-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (32). I-200

[0724] Peak B: 1H NMR(400MHz,DMSO-d6)δ7.69(d,J=2.0Hz,1H),7.50(dd,J=8.4,2.1Hz,1H), 7.29(d,J=8.4Hz,1H),6.87(s,3H),6.01(s,1H),5.59(s,1H),4.49(d,J=14 .9Hz,1H),4.13(dd,J=13.6,4.9Hz,1H),3.91-3.78(m,3H),3.62(ddd,J=12 .2,9.4,4.9Hz,1H),2.19(s,4H),1.82(dp,J=10.1,3.6,3.1Hz,2H); ESI-MS m / z calculated 396.0, found 397.0 (M+1) + Retention time: 0.8 min; [α] = +79.9 (c = 1, MeOH) 7.1 mg / mL; (S)-4-(3-(4-bromo-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (33). I-201

[0725]

[0726] 4-[(3S)-3-(5-Bromo-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine I-245

[0727] 1 H NMR (300 MHz, DMSO-d6) 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 calculated 396.03, found 397.01 (M+1) + ; Retention time: 0.65 minutes; [α] D =+66.68° (c=0.5, MeOH).

[0728] Example 3

[0729] Synthesis Scheme 3: (R)-4-(2-(2-chlorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine and (S)-4-(2-(2-chlorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine

[0730]

[0731] (a) 2-Amino-4-chloro-6-methylpyrimidine, nBuOH, 200°C, microwave; (b) Chiral HPLC separation

[0732] Formation of (±)-(2-(2-chlorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (34)

[0733] A suspension of 4-chloro-6-methyl-pyrimidin-2-amine (3.02 g, 21.03 mmol) and 2-(2-chlorophenyl)azepane (3.99 g, 19.01 mmol) in n-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 diethyl ether to give 3.61 g of racemic product: 1 H NMR (400 MHz, CDCl3) 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 calculated 316.15, found 317.2 (M+1) + ; Retention time: 0.8 minutes.

[0734] The racemic mixture was separated by analytical chiral HPLC (AD-H, 4.6 x 100 mm, 40% MeOH, 5 mM ammonia, 60% CO2, isocratic injection of 10 uM in 1 mg / mL methanol at 5 ml / min. 120 bar. UV 254 nM). RT Peak A 0.432 min, ee 97.2%, Peak B at 0.479 min.

[0735] Peak A: 2.10 g, 97.2% ee; optical rotation: [□] D =-0.096 (c=1.04, MeOH); 1H NMR (400 MHz, CDCl3) 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), 1.97-1.82 (m, 2H), 1.76-1.51 (m, 2H), 1.51-1.31 (m, 2H); ESI-MS m / z calculated 316.15, found 317.24 (M+1) + Retention time: 0.83 minutes. (R)-4-(2-(2-chlorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (35) I-13

[0736] Peak B: 2.09g, 96%ee; optical rotation: [□] D =+1.373 (c=1.02, MeOH); 1 H NMR (400 MHz, CDCl3) 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 calculated 316.15, found 317.2 (M+1) + Retention time: 0.82 minutes. (S)-4-(2-(2-chlorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (36) I-14

[0737] The following analogs were prepared according to Synthetic Scheme 3:

[0738]

[0739] (R)-4-(2-(2-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (37) I-11 and (S)-4-(2-(2-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (38) I-12

[0740] Peak A from SFC chiral separation: 1H NMR (400 MHz, CDCl3) 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 calculated 312.20, found 313.13 (M+1) + ; Retention time: 0.78 minutes. (38) I-12

[0741] Peak B from SFC chiral separation: 1 H NMR (400 MHz, CDCl3) 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 calculated 312.12, found 313.13 (M+1) + ; Retention time: 0.8 minutes. (37) I-11

[0742]

[0743] (R)-4-(2-(2-bromo)azepan-1-yl)-6-methylpyrimidin-2-amine (41) I-2 and (S)-4-(2-(2-bromo)azepan-1-yl)-6-methylpyrimidin-2-amine (42) I-3

[0744] Peak A from SFC chiral separation: 1 H NMR (400 MHz, CDCl3) 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, 1H), 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 calculated 360.09, found 361.12 (M+1) + ; Retention time: 0.91 min. (41)I-2

[0745] Peak B from SFC chiral separation:1 H NMR (400 MHz, CDCl3) 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 calculated 360.09, found 361.12 (M+1) + ; Retention time: 0.93 minutes. (42)I-3

[0746]

[0747] (±)-4-methyl-6-(2-(2-(methylthio)phenyl)azepan-1-yl)pyrimidin-2-amine (43) I-5

[0748] 1 H 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 calculated 328.17, found 329.11 (M+1) + ; Retention time: 0.75 minutes.

[0749]

[0750] (±)-4-methyl-6-(2-(2-(methyl)phenyl)azepan-1-yl)pyrimidin-2-amine (44) I-6

[0751] 1H NMR (400 MHz, methanol-d4) δ 7.19-6.99 (m, 4H), 2.46 (s, 3H), 2.27 (ddd, J = 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 calculated 296.20, found 297.14 (M+1) + ; Retention time: 0.74 minutes.

[0752]

[0753] (±)-4-(2-(2,4-dichlorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (45) I-1

[0754] 1 H 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 calculated 350.11, found 351.11 (M+1) + ; Retention time: 3.13 minutes.

[0755]

[0756] (±)-4-methyl-6-(2-phenylazepan-1-yl)pyrimidin-2-amine (45) I-4

[0757] 1 H NMR(400MHz,MeOD)δ7.48-7.17(m,5H),6.39-5.94(2s,1H),4.04-3.36(m,1H),2.52( td,J=14.5,6.2Hz,1H),2.27(d,J=61.1Hz,3H),2.04-1.79(m,4H),1.76-1.05(m,3H).

[0758]

[0759] (±)-4-(2-(2-chlorophenyl)azepan-1-yl)-6-isopropylpyrimidin-2-amine I-16

[0760] 1H NMR(400MHz,DMSO-d6)δ7.47-7.34(m,1H),7.34-7.17(m,3H),5.57(s,1H),5. 46(s,2H),5.21(s,1H),4.55(d,J=14.9Hz,1H),3.55-3.40(m,1H),2.57-2.52( m,1H),2.34(ddd,J=13.8,8.1,5.0Hz,1H),1.98(t,J=11.2Hz,1H),1.92-1.64( m,3H),1.61-1.18(m,3H),1.08(d,J=6.9Hz,3H),1.04(d,J=6.9Hz,3H); ESI-MS m / z found 345.

[0761]

[0762] (±)-4-(2-(2-chlorophenyl)azepan-1-yl)-6-ethylpyrimidin-2-amine I-17

[0763] 1 H NMR (400 MHz, DMSO-d6) 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 (m, 1H), 2.52-2.49 (m, 1H), 2.38-2.22 (m, 3H), 2.01-1.64 (m, 2H), 1.59-1.21 (m, 4H), 1.03 (t, J = 7.5 Hz, 3H); ESI-MS m / z found 331.

[0764] Example 4

[0765] Synthesis Scheme 4: (±)-4-(3-(5-amino-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (46) I-71

[0766]

[0767] (a) Zinc, NH4Cl, 2% TPGS-750-M in water, 75°C; (b) SFC chiral separation

[0768] Formation of (R)-4-(3-(5-amino-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (47) and (S)-4-(3-(5-amino-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (48)

[0769] 4-[3-(2-Chloro-5-nitro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine, 24, (1.00 g, 2.75 mmol), NHCl (0.31 g, 5.85 mmol) and Zn (0.87 g, 13.36 mmol) were stirred in a 2% aqueous solution of TPGS-750-M (28 mL). The reaction mixture was stirred vigorously and heated to 75° C. for 24 hours. The mixture was cooled to room temperature and diluted into saturated aqueous NaHCO and dichloromethane. The organic phase was dried (MgSO), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using a 40 g isco GOLD column using 0-50% (20% MeOH-CHCl / CHCl) to give 390 mg of compound 46 as a racemic mixture. SFC chiral separation of the racemic mixture: prepared in 50% IPA, 50% hexanes, 0.2% diethylamine (on AD-H) to afford the individual stereoisomers.

[0770] Peak A - 99% pure by chiral HPLC; (R)-4-[3-(5-amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (47): high temperature (360K) 1 H NMR (400 MHz, DMSO-d6) δ 7.01 (d, J = 8.5 Hz, 1H), 6.52 (d, J = 2.7 Hz, 1H), 6.47 (dd, J = 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 calculated 333.14, found 334.26 (M+1) + ; Retention time: 0.51 minutes; [□] D =-118.67(c=12mg / 4mL MeOH). I-86

[0771] Peak B - 99.9% pure by chiral HPLC; (S)-4-[3-(5-amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (48): high temperature (360K) 1 H NMR (400MHz, DMSO-d6) δ7.01(dd,J=8.5,1.5Hz,1H),6.52(d,J=2.5Hz,1H),6.47(dt,J=8.5,2.1Hz,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=13.4,5.0,1.5Hz,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 calculated 333.14, found 334.26 (M+1) + ; Retention time: 0.51 minutes; [□] D =+175(c=8mg / 4mL MeOH). I-87

[0772] The following analogs were prepared according to Synthetic Scheme 4:

[0773]

[0774] (±)-4-[3-(4-amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (49) I-140

[0775] High temperature (360K) 1 H NMR (400 MHz, DMSO-d6) 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 calculated 333.14, found 334.26 (M+1) + ; Retention time: 0.51 minutes.

[0776] Example 5

[0777] Synthesis Scheme 5: (±)-N-[4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-3-chloro-phenyl]methanesulfonamide I-139, I-179 and I-296

[0778]

[0779] (a) Methanesulfonyl chloride, NEt3, THF; (b) SFC chiral separation

[0780] Formation of (±)-3-(2-chloro-5-nitrophenyl)-1,4-oxazepane(50)I-139

[0781] To a solution of 4-[3-(4-amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine, 49, (0.034 g, 0.103 mmol) and triethylamine (0.050 mL, 0.360 mmol) in THF (1.5 mL) was added methanesulfonyl chloride (0.009 mL, 0.113 mmol). The reaction mixture was stirred at room temperature overnight. An additional 5 μL of methanesulfonyl chloride was added. After 20 minutes, the reaction mixture was concentrated in vacuo. Purification was performed on a reverse phase 50 g ISCO c18-aq column eluting with 0.1% TFA / H2O and 0.1% TFA / CH3CN. Pure fractions were concentrated in vacuo and then dissolved in MeOH and passed through 2 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) 1 H NMR (400 MHz, DMSO-d6) 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 calculated 411.11, found 412.24 (M+1) + ; Retention time: 0.56 minutes.

[0782] Chiral HPLC separation to obtain each enantiomer

[0783] Peak A:1 H NMR(400MHz, DMSO-d6)δ9.66(s,1H),7.28-7.23(m,2H),7.13(dd,J=8.5,2.2Hz,1H),5.59(s,1H),5.46(s,2H),5.39(s,1H),4.59(d,J=14.9Hz,1H ),4.09(dd,J=13.5,5.0Hz,1H),3.93-3.85(m,1H),3.71(dd,J=13.5,10. 1Hz,1H),3.66-3.49(m,2H),2.99(s,3H),2.01(s,3H),1.81-1.70(m,2H). I-179

[0784] Peak B: 1 H NMR(400MHz,DMSO-d6)δ7.33-7.22(m,2H),7.13(dd,J=8.5,2.2Hz,1H),5.5 9(s,1H),5.46(s,2H),5.44-5.34(m,1H),4.59(d,J=15.2Hz,1H),4.09(dd, J=13.4,5.0Hz,1H),3.93-3.84(m,1H),3.71(dd,J=13.5,10.1Hz,1H),3.67 -3.49(m,2H),2.99(s,3H),2.01(s,3H),1.77(ddt,J=10.2,8.0,3.4Hz,2H). I-296

[0785] Example 6

[0786] Synthesis Scheme 6: (±)-N-[4-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-3-chloro-phenyl]methanesulfonamide (51) I-282

[0787]

[0788] (a) 3-Methyloxetane-3-carboxylic acid, iPr2NEt, HATU, DMF.

[0789] Formation of (±)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-3-methyloxetane-3-carboxamide (51) I-282

[0790] To a solution of 4-[3-(4-amino-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine (0.05 g, 0.15 mmol), 3-methyloxetane-3-carboxylic acid (0.02 g, 0.16 mmol) and N,N-diisopropylethylamine (0.05 mL, 0.30 mmol) in DMF (1 mL) was added N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanium 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 reverse phase preparative HPLC (CH3CN / 0.1% TFA aqueous solution). The fraction containing the desired product was basified with a saturated NaHCO3 aqueous solution wash and extracted with dichloromethane. The organic phase was passed through a phase separator and concentrated in vacuo to give the desired product.

[0791] The following analogs were prepared according to Synthetic Scheme 6:

[0792]

[0793] (3R)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-tetrahydrofuran-3-carboxamide (52) I-280

[0794] (racemic mixture at the 3-position of oxazepane) 1 H NMR (400MHz, CDCl3) δ7.74(s,1H),7.54(s,1H),7.30-7.21(m,1H),7.15(d,J =8.4Hz,1H),5.53(s,1H),4.66(s,2H),4.29(dd,J=13.6,5.0Hz,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=14.3Hz,3H).-ESI-MS m / z calculated 431.17, found 432.18 (M+1) + ; Retention time: 0.57 minutes

[0795]

[0796] (3S)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-tetrahydrofuran-3-carboxamide (53) I-281

[0797] (racemic mixture at the 3-position of oxazepane) 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 calculated 431.17, found 432.14 (M+1) + ; Retention time: 0.57 minutes

[0798]

[0799] (±)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-2,2-difluoropropionamide (54) I-228

[0800] 1 H NMR (400 MHz, CDCl3) 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 calculated 425.1, found 426.2 (M+1) + ; Retention time: 0.64 minutes.

[0801]

[0802] (±)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-2,2-difluoroacetamide (55) I-278

[0803] 1H NMR (400 MHz, CDCl3) 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 calculated 411.1, found 412.1 (M+1) + ; Retention time: 0.6 minutes.

[0804]

[0805] (±)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-3-fluorotetrahydrofuran-3-carboxamide (56) I-279

[0806] 1 H NMR (400MHz, CDCl3) δ8.17(d,J=7.9Hz,1H),7.81(d,J=7.8Hz,1H),7.32(td, J=8.3,2.2Hz,1H),7.20(d,J=8.5Hz,1H),5.53(s,1H),4.61(s,2H),4.30(dd, J=13.6,5.0Hz,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 calculated 449.2, found 450.1 (M+1) + ; Retention time: 0.6 minutes.

[0807] The following analogs were prepared according to Scheme 6 using 4-(3-(5-amino-2-chlorophenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine 46 as starting material:

[0808]

[0809] (±)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]-2-(oxetane-3-yl)acetamide (57) I-185

[0810] 1 H 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 calculated 431.2, found 432.1 (M+1) + ; Retention time: 0.55 minutes.

[0811]

[0812] (±)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]cyclopropanecarboxamide (58) I-241

[0813] Heating (360K) 1 H NMR (300 MHz, DMSO-d6) 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 calculated 401.2, found 402.2 (M+1) + ; Retention time: 0.62 minutes.

[0814]

[0815] (S)-N-[3-[(3S)-4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]-3-hydroxy-propionamide (59) I-283

[0816] A similar procedure was used to obtain the racemic material, which was then purified by chiral HPLC (column (OJ-H 20x250m), mobile phase (80% hexanes / 20% IPA / 0.2% diethylamine), flow rate 20 mL / min).

[0817] Peak B:ee:91%; [α] D (c=0.5,MeOH)+32.4; 1 H NMR (300 MHz, methanol-d4) 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 calculated 405.2, found 406.2 (M+1) + ; Retention time: 0.58 minutes.

[0818]

[0819] N-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenyl)-2,2,2-trifluoroacetamide (60) I-177

[0820] A similar procedure was used to obtain the racemic material, which was then purified by chiral HPLC (column (OJ-H 20x250m), mobile phase (80% hexanes / 20% IPA / 0.2% diethylamine), flow rate 20 mL / min).

[0821] Peak B:ee:99%; [α] D (c=0.5,MeOH)+157.3; 1 H NMR (300 MHz, methanol-d4) 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 calculated 429.1, found 429.9 (M+1) + ; Retention time: 0.65 minutes.

[0822]

[0823] (±)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]-2-(dimethylamino)acetamide (61) I-168

[0824] Heating (360K) 1 H NMR (300 MHz, DMSO-d6) 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 calculated 418.2, found 419.1 (M+1) + ; Retention time: 0.58 minutes.

[0825]

[0826] (±)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]oxetane-2-carboxamide (62) I-184

[0827] 1 H NMR (300 MHz, methanol-d4) 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 calculated 417.2, found 418.0 (M+1) + ; Retention time: 0.6 minutes.

[0828]

[0829] (±)-N-[3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenyl]-3-hydroxy-3-methyl-butyramide (63) I-251

[0830] 1 H NMR (300MHz, methanol-d4) δ7.75 (t, J = 10.0Hz, 1H), 7.48-7.40 (m, 1H), 7.39-7.29 (m, 1H), 6.52 (s, 0. 5H),6.08(dd,J=10.3,5.3Hz,0.5H),5.65(d,J=3.3Hz,0.5H),5.35(dd,J=10.5,5.1Hz,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 calculated 433.2, found 434.2 (M+1) + ; Retention time: 0.59 minutes.

[0831] Example 7

[0832] Synthesis Scheme 7: (±)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-2-hydroxy-2-methylpropionamide I-277

[0833]

[0834] (a) 2-Hydroxy-2-methylpropionamide, NaOtBu, tBuXPhos Pd G3, tBuOH, 60°C; (b) SFC chiral separation

[0835] Formation of (S)-N-(4-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-3-chlorophenyl)-2-hydroxy-2-methylpropionamide (64) I-276

[0836] In a microwave tube, a mixture of 4-[3-(4-bromo-2-chloro-phenyl)-1,4-oxazepan-4-yl]-6-methyl-pyrimidin-2-amine, 31 (0.77 g, 1.86 mmol), 2-hydroxy-2-methyl-propionamide (0.45 g, 4.36 mmol), sodium tert-butoxide (0.56 g, 5.78 mmol), and [2-(2-aminophenyl)phenyl]-methylsulfonyloxy-palladium; di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane (tBuXPhos Pd G3) (0.06 g, 0.08 mmol) in 2-methyl-2-propanol (14 mL) was evacuated and backfilled with nitrogen three times. The tube was then heated to 60°C 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 obtained residue is passed through reverse phase silica gel chromatography using C-18 (150 g) ISCO column with 0-90% CH CN / H O (ammonium formate conditioning agent) elution. The pure fractions are concentrated in a vacuum, diluted with dichloromethane, and washed with water. The organic phase is passed through a phase separator and concentrated in a vacuum to obtain 207 mg of the desired product. The racemic mixture is subjected to SFC chiral purification (column-IA, 20x250 mm mobile phase-20% MeOH (5 mM ammonia), 80% CO flow rate-80 mL / min).

[0837] Peak B: 1 H NMR (400 MHz, CDCl3) 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); ESI-MS m / z calculated 419.2, found 420.2 (M+1) + ; Retention time: 0.58 minutes.

[0838] Example 8

[0839] Synthesis Scheme 8: (±)-4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (69) I-311

[0840]

[0841] (a) TMS-diazomethane, toluene, methanol; (b) NaBH4, MeOH; (c) Dess-Martin periodinane, dichloromethane; (d) 4A molecular sieve, 3-((tributylstannyl)methoxy)propane-1-amine, CH2Cl2; then 2,6-lutidine, Cu(OTf)2, hexafluoroisopropanol, CH2Cl2; (e) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (f) SFC chiral separation

[0842] Formation of methyl 2-chloro-5-(methylsulfonyl)benzoate (65)

[0843] To a solution of 2-chloro-5-methylsulfonyl-benzoic acid (3.0 g, 12.8 mmol) in toluene (45 mL) and MeOH (10 mL) was added TMS-diazomethane (10.7 mL 2M in hexanes, 21.4 mmol) dropwise. The reaction mixture was stirred for 3 hours and the solvent was concentrated in vacuo to give 3 grams of the desired product as a brown fluffy solid which was used without further purification: 1 H NMR (400 MHz, DMSO-d6) 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 calculated 247.99, found 249.12 (M+1) + ; Retention time: 0.71 minutes.

[0844] Formation of (2-chloro-5-(methylsulfonyl)phenyl)methanol (66)

[0845] To a suspension of methyl 2-chloro-5-methylsulfonyl-benzoate, 65, (3.0 g, 12.1 mmol) in EtOH (45 mL) was added NaBH4 (1.83 g, 48.4 mmol). The reaction mixture was stirred at room temperature for 1 hour and then heated to 50°C to dissolve the mixture. After 3 hours, the mixture was quenched by slowly adding saturated aqueous NH4Cl solution. The aqueous phase was extracted twice with EtOAc. The combined organic phases were washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to give 2.5 g of the desired product as an orange oil. The crude residue was purified by silica gel chromatography using a 40 g ISCO column using a 0-30% EtOAc / CH2Cl2 gradient to give 2.0 g of the product as a white solid: ESI-MS m / z calculated 219.99, found 221.06 (M+1) + ; Retention time: 0.61 minutes.

[0846] Formation of 2-chloro-5-(methylsulfonyl)benzaldehyde (67)

[0847] (2-Chloro-5-methylsulfonyl-phenyl)methanol, 66, (1.00 g, 4.50 mmol) was dissolved in dichloromethane (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 into saturated aqueous NaHCO3 and extracted twice with EtOAc. The combined organic phases were washed with saturated aqueous NaHCO3, dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by silica gel chromatography using a 40 g ISCO column using a 0-20% EtOAc / CH2Cl2 gradient to give 760 mg of the desired product: 1 H NMR (400MHz, DMSO-d6) δ 10.36 (s, 1H), 8.31 (d, J = 2.4Hz, 1H), 8.20 (dd, J = 8.4, 2.4Hz, 1H), 7.94 (d, J = 8.4Hz, 1H), 3.32 (s, 3H).

[0848] Formation of 3-(2-chloro-5-(methylsulfonyl)phenyl)-1,4-oxazepane (68) To a solution of 3-(tributylstannylmethoxy)propan-1-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 molecular sieves, and diluted with dichloromethane (25 mL).

[0849] 2,6-lutidine (0.28 mL, 2.39 mmol) was added to a separate flask containing hexafluoroisopropanol (7 mL), followed by Cu(OTf)2 (0.85 g, 2.34 mmol). The mixture was stirred for 1 hour, and then the imine solution prepared above was added in one portion. The reactants were stirred at room temperature for 3 days. The mixture was diluted with 60 mL of a 2:1 mixture of saturated NaHCO3 aqueous solution and 10% ammonium hydroxide. After stirring for 30 minutes, the organic layer was removed and washed twice with saturated NaHCO3 aqueous solution and then with brine. The organic layer was passed through a phase separation funnel and concentrated in vacuo. The resulting residue was purified by reverse phase silica gel chromatography using an ISCO-100 g c18-aq column (eluted with 0.1% TFA / H2O and 0.1% TFA / CH3CN). The fraction containing the product was concentrated in vacuo and the residue was diluted with dichloromethane and neutralized with saturated NaHCO3 aqueous solution. The organic phase was passed through a phase separator and concentrated in vacuo. 1 H NMR showed the desired product and additional impurities. The product was used without further purification:1 H NMR (400 MHz, DMSO-d6) 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); ESI-MS m / z calculated 390.05, found 390.09 (M+1) + ; Retention time: 0.50 minutes.

[0850] Formation of 4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (69)

[0851] To a solution of 3-(2-chloro-5-methylsulfonyl-phenyl)-1,4-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 to 150° C. for 18 hours. The reaction mixture was cooled to room temperature and the material was directly loaded onto a 50 g ISCO c18-aq column and purified by reverse phase silica gel chromatography using a 50 g ISCO column eluted 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 NaHCO3, passed through a phase separator, and the resulting organic phase was concentrated in vacuo to give 84 mg of a brown solid: high temperature (360 K) 1 H NMR (400MHz, DMSO-d6) δ7.85-7.73 (m, 2H), 7.71 (d, J = 8.3Hz, 1H), 5.7 5-5.54(m,2H),5.50-5.34(m,2H),4.48(d,J=14.9Hz,1H),4.11(dd,J=13.5,4.9Hz,1H),3. 92-3.65(m,3H),3.67-3.50(m,1H),3.18-3.11(m,3H),2.03(d,J=5.4Hz,3H),1.80(s,2H).

[0852] SFC chiral separation of the racemic mixture: prepared in 50% IPA, 50% hexanes, 0.2% diethylamine on AD-H.

[0853] Peak A: (R)-4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (70), 96.4% ee as determined by HPLC; heating (360K) 1 H NMR (400MHz, DMSO-d6) δ7.81 (ddd, J=8.3, 2.3, 1.1Hz, 1H), 7.78 (d, J=2.3Hz, 1H), 7.71(dd,J=8.3,1.2Hz,1H),5.70(s,1H),5.62(dd,J=9.9,4.8Hz,1H),5.43(s,2H) ,4.48(d,J=15.4Hz,1H),4.11(dd,J=13.4,4.9Hz,1H),3.97-3.68(m,3H),3.66-3. 52(m,1H),3.16(d,J=1.2Hz,3H),2.04(d,J=1.0Hz,3H),1.89-1.70(m,2H); ESI-MS m / z calculated 396.10, found 397.25 (M+1) + ; Retention time: 0.56 minutes; [α] D =-42.40 (c=5mg / 2mL MeOH). I-102

[0854] Peak B (S)-4-(3-(2-chloro-5-(methylsulfonyl)phenyl)-1,4-oxazepan-4-yl)-6-methylpyrimidin-2-amine (71), 98+% ee by HPLC; heating (360K) 1 H NMR (400MHz, DMSO-d6) δ7.81 (dd, J=8.3, 2.3Hz, 1H), 7.78 (d, J=2.2Hz, 1H), 7.71 (d,J=8.3Hz,1H),5.70(s,1H),5.62(dd,J=9.9,4.9Hz,1H),5.42(s,2H),4.48(d, J=15.2Hz,1H),4.11(dd,J=13.5,4.9Hz,1H),3.94-3.70(m,3H),3.60(ddd,J=12. 0,9.5,4.7Hz,1H),3.15(s,3H),2.04(s,3H),1.80(dt,J=8.3,4.2Hz,2H); ESI-MS m / z calculated 396.10, found 397.20 (M+1) + ; Retention time: 0.55 minutes; [□]D =+77.82(c=5.5mg / 2mL MeOH). I-103

[0855] The following analogs were prepared according to Synthetic Scheme 8:

[0856]

[0857] 1-(3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenyl)pyrrolidin-2-one (72) I-119

[0858] 1 H NMR (400MHz, DMSO-d6) δ7.76(d,J=2.7Hz,1H),7.45(dd,J=8.7,2.7Hz,1H),7.39(d,J =8.8Hz,1H),5.59(s,1H),5.42(s,3H),4.63(d,J=15.1Hz,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 calculated 401.16, found 402.0 (M+1) + ; Retention time: 0.65 minutes.

[0859] Example 9

[0860] Synthesis Scheme 9: (±)-4-(2-(2,5-dimethoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (77) I-25

[0861]

[0862] (a) DMF, POCl3, CH2Cl2, 0°C to 40°C; (b) 2,5-dimethoxyphenylboronic acid, Pd(Ph3P)2Cl2, DME, 50°C; (c) Pd / C, HOAc, EtOAc, MeOH; (d) EtMgBr, THF, 0°C; (e) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (f) SFC chiral separation

[0863] Formation of 7-chloro-2,3,4,5-tetrahydro-1H-azacycloheptatriene-1-carbaldehyde (73)

[0864] To be equipped with overhead stirrer, temperature probe, addition funnel, nitrogen inlet and reflux condenser 3- neck 3L round bottom flask, be charged with DMF (360mL, 4.65mol) in dichloromethane (500mL) and stir for 5 minutes, and then be cooled to 0 ℃.Last 60 minutes, add POCl3 (220mL, 2.36mol) in dichloromethane (300mL), while maintaining internal temperature below 7 ℃.Reaction mixture is warmed to 40 ℃ (observation colorless solution becomes light orange), stirred at this temperature for 45 minutes.Under reflux, last 45 minutes and add azepane-2-one (85g, 751.2mmol) (observation Tmax 45 ℃) in dichloromethane (450mL).The reaction mixture obtained is stirred at this temperature for 3h, and now HPLC-analysis discloses the exhaustion of starting material.Reaction mixture is cooled to ambient temperature, poured into crushed ice (3L), and then lasts 12h and reaches ambient temperature. The aqueous layer was separated and alkalized with solid K2CO3 until pH 9, which was warmed to ambient temperature and stirred at this temperature for 18h. The mixture was diluted with dichloromethane (2L) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (1L) and the combined organic extracts were washed with water (100mL) and brine (200mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel plug using 0% → 30% ethyl acetate / heptane (which contains 1% Et3N). The fractions containing the desired product were collected and concentrated under reduced pressure to obtain 7-chloro-2,3,4,5-tetrahydroazacycloheptatriene-1-carboxaldehyde (110g, 92%) as a clear colorless oil.

[0865] Formation of 7-(2,5-dimethoxyphenyl)-2,3,4,5-tetrahydro-1H-azacycloheptatriene-1-carbaldehyde (74)

[0866] Under nitrogen, a 2-neck round-bottom flask was charged with 7-chloro-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde, 73 (3.00 g, 18.80 mmol), (2,6-dimethoxyphenyl)boronic acid (4.45 g, 24.44 mmol), DME (24.67 mL), and bis(triphenylphosphine)palladium(II) dichloride (0.53 g, 0.75 mmol). The reaction mixture was stirred at 50°C overnight. The mixture was diluted with water and dichloromethane. The layers were separated by a phase separator, and the organic phase was concentrated in vacuo. The crude residue was purified by silica gel chromatography using an ISCO 12g GOLD column; 10-100% EtOAc in heptane) to a light yellow oil. 1H NMR (300 MHz, DMSO-d6) 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); ESI-MS m / z calculated 261.14, found 262.15 (M+1) + ; Retention time: 0.84 minutes.

[0867] Formation of 2-(2,5-dimethoxyphenyl)azepane-1-carbaldehyde (75)

[0868] To a solution of 7-(2,6-dimethoxyphenyl)-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde, 74, (3.00 g, 11.48 mmol) in MeOH (30 mL) and EtOAc (30 mL) was added HOAc (9 mL) and Pd / C (0.24 g, 2.30 mmol). After vacuum purification three times, the flask was loaded with a hydrogen balloon. 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.

[0869] Formation of (±)-2-(2,5-dimethoxyphenyl)azepane (76)

[0870] To a solution of 2-(2,4-dimethoxyphenyl)azepane-1-carbaldehyde, 75, (1.80 g, 6.51 mmol) in THF (50 mL) was added ethylmagnesium bromide (2.21 g, 2.17 mL of a 3M solution in diethyl ether, 6.51 mmol) at 0 ° C. The mixture was stirred at 0 ° C for 3 hours. The mixture was carefully quenched by adding 2N NaOH solution and then extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4, filtered and concentrated in vacuo. The crude residue was purified by ISCO using a methanol / dichloromethane gradient.

[0871] Formation of (R)-4-(2-(2,5-dimethoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (78) and (S)-4-(2-(2,5-dimethoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (79)

[0872] To a mixture of solid 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) in a bottle was added EtOH (2 mL). The bottle was placed on a hot plate and heated at 180° C. for 2 hours without a cap. The crude residue was purified by silica gel chromatography using a 40 g ISCO column eluted with a 20% MeOH-dichloromethane / dichloromethane gradient to give 32 mg of the desired product: 1 H NMR (300 MHz, DMSO-d6) 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 calculated 342.21, found 343.32 (M+1) + ; Retention time: 0.72 minutes.

[0873] The racemate (4.0 g) was subjected to SFC separation (column: IC, 4.6 x 100 mm IC, 20 x 250 mm mobile phase: 40% EtOH (5 mM ammonia), 60% CO 2 40% EtOH (5 mM ammonia), 60% CO 2 ) to give:

[0874] Peak A: 1.61 g (R)-4-(2-(2,5-dimethoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (78): ee = 98%; [α] D (c=1.0,MeOH)+111.98; 1 H NMR (300 MHz, DMSO-d6) 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 calculated 342.21, found 343.27 (M+1) + ; Retention time: 0.74 minutes. I-40

[0875] Peak B: 1.21 g (S)-4-(2-(2,5-dimethoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (79): ee = 96%; [α] D (c=1.0, MeOH)-147.32; 1 H NMR (300 MHz, DMSO-d6) 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 calculated 342.21, found 343.32 (M+1) + ; Retention time: 0.76 minutes. I-41

[0876] The following analogs were prepared according to Synthetic Scheme 9:

[0877]

[0878] (±)-4-(2-(2-chloro-5-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (80) I-117

[0879] 1 H NMR (300 MHz, DMSO-d6) 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, 0H), 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 calculated 346.16, found 347.17 (M+1) + ; Retention time: 0.72 minutes.

[0880]

[0881] (R)-4-(2-(2-chloro-5-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (81) I-135 and (S)-4-(2-(2-chloro-5-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (81) I-136

[0882] 4-[2-(2-chloro-5-methoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (450 mg, 1.289 mmol) was separated by SFC. SFC conditions: Column: IC, 20 x 250 mm; Mobile phase: 30% MeOH (5 mM ammonia), 70% CO2; Flow rate: 75 mL / min; Concentration: ~40 mg / mL (MeOH); Injection volume: 500 μL; Wavelength: 214 nm; Method type: Isocratic Peak A: [α] D (c=0.5,MeOH)+74.56; 99.4%ee

[0883] (R)-4-[2-(2-Chloro-5-methoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (81): 1 HNMR (300 MHz, DMSO-d6) 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 calculated 346.16, found 347.2 (M+1) + ; Retention time: 0.72 minutes. I-135

[0884] Peak B: [α] D (c=0.5,MeOH)-76.80; 99%ee

[0885] (S)-4-[2-(2-Chloro-5-methoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (82) (200 mg, 89%): 1 H NMR(300MHz,DMSO-d6)δ7.78(s,1H),7.39(m,2H),7.01-6.77(m,1H),6.62(d,3.0Hz,1 H),6.49(s,0.5H),5.72(dd,J=12.5,5.1Hz,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), 2.05-0.97 (m, 8H); ESI-MS m / z calculated 346.16, found 347.15 (M+1)+ ; Retention time: 0.72 minutes. I-136

[0886]

[0887] (±)-4-[2-(2-Fluoro-6-methoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (83) I-50

[0888] 1 H NMR (300 MHz, DMSO-d6) 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 calculated 330.19, found 331.29 (M+1) + ; Retention time: 0.72 minutes.

[0889]

[0890] (±)-4-[2-(4-chlorophenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (I-43)

[0891] 1 H NMR (300 MHz, DMSO-d6) 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 calculated 316.15, found 317.24 (M+1) + ; Retention time: 0.72 minutes.

[0892]

[0893] (±)-4-[2-(3-chlorophenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (I-44)

[0894] 1H NMR (300 MHz, DMSO-d6) 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); ESI-MS m / z calculated 316.15, found 317.19 (M+1) + ; Retention time: 0.72 minutes.

[0895]

[0896] (±)-4-[2-(3-Fluorophenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine I-29

[0897] High temperature (360K) 1 H NMR (400 MHz, DMSO-d6) 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 calculated 300.18, found 301.21 (M+1) + ; Retention time: 0.64 minutes.

[0898]

[0899] (±)-4-[2-(2,4-dimethoxyphenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (84) I-51

[0900] 1H NMR (300 MHz, DMSO-d6) 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 calculated 342.20, found 343.32 (M+1) + ; Retention time: 0.72 minutes.

[0901]

[0902] (±)-4-(2-cyclopentylazepan-1-yl)-6-methylpyrimidin-2-amine I-9

[0903] 4-Chloro-6-methyl-pyrimidin-2-amine (0.094 g, 0.657 mmol), 2-cyclopentylazepane (0.100 g, 0.598 mmol) and i A suspension of Pr2NEt (0.230 mL, 1.320 mmol) in IPA (0.6 mL) was sealed in a microwave tube and irradiated at 160° C. for 2 hours. The mixture was concentrated in vacuo and purified by reverse phase chromatography (0.1% TFA / acetonitrile). The material was converted to the HCl salt to give 46 mg of the desired product: 1 H 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 calculated 274.22, found 275.18 (M+1) + ; Retention time: 2.84 minutes

[0904]

[0905] (±)-4-methyl-6-[2-(4-pyridyl)azepan-1-yl]pyrimidin-2-amine I-35

[0906] ESI-MS m / z calculated 283.18, found 284.22 (M+1)+ ; Retention time: 2.14 minutes.

[0907]

[0908] (±)-4-[2-(4-Fluorophenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine I-34

[0909] High temperature (360K) 1 H NMR (400 MHz, DMSO-d6) 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 calculated 300.18, found 301.22 (M+1) + ; Retention time: 2.97 minutes.

[0910]

[0911] (±)-4-methyl-6-[2-(p-tolyl)azepan-1-yl]pyrimidin-2-amine I-33

[0912] High temperature (360K) 1 H NMR (400 MHz, DMSO-d6) 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 calculated 296.20, found 297.25 (M+1) + ; Retention time: 3.07 minutes.

[0913]

[0914] (±)-4-[2-(4-Methoxyphenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine I-23 High temperature (360K) 1H NMR (400 MHz, DMSO-d6) 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 calculated 296.20, found 297.25 (M+1) + ; Retention time: 3.07 minutes.

[0915] Example 10

[0916] Synthesis Scheme 10: (±)-4-[2-(2,5-dimethoxy-4-pyridinyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (88) I-116

[0917]

[0918] (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-6-methylpyrimidine, NMP, 150°C; (f) SFC chiral separation

[0919] Formation of 7-(2,5-dimethoxy-4-pyridyl)-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde (85)

[0920] Under nitrogen, a 2-neck rb flask was charged with 7-chloro-2,3,4,5-tetrahydroazacycloheptatriene-1-carboxaldehyde, 73, (0.79 g, 4.95 mmol), (2,5-dimethoxy-4-pyridyl)boronic acid (1.00 g, 5.46 mmol) in DME (10 mL), followed by NaHCO (8 mL 1.2 M solution, 9.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.14 g, 0.20 mmol). Stirred overnight at 60 ° C. Water and dichloromethane were added. The layers were separated by a phase separator and the organic matter was concentrated in vacuo after the second extraction. Purified by silica gel chromatography (40 g GOLD column; 10-100% EtOAc / heptane gradient) to give 1 g (47%) of the desired product: 1H NMR (300 MHz, CDCl3) 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 calculated 262.13, found 263.07 (M+1) + ; Retention time: 0.75 minutes.

[0921] Formation of 2-(2,5-dimethoxy-4-pyridyl)azepane-1-carbaldehyde (86)

[0922] To a solution of 7-(2,5-dimethoxy-4-pyridyl)-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde, 85, (1.0 g, 3.8 mmol) in MeOH (20 mL) and EtOAc (20 mL) was added formic acid (1.7 g, 37.0 mmol) and Pd / C (40 mg, 0.4 mmol) under N2 atmosphere. The reaction mixture was then charged with H2 (balloon) and stirred at room temperature overnight. The mixture was filtered through celite and the solvent was evaporated. The residue was purified by silica gel column (40 g) in ISCO, eluting with a 0% to 50% EtOAc / heptane gradient. The desired fractions were collected and evaporated to give 1.0 g (51%) of the desired product: ESI-MS m / z calculated 264.15, found 265.14 (M+1) + ; Retention time: 0.72 minutes.

[0923] Formation of 2-(2,5-dimethoxy-4-pyridyl)azepane (87)

[0924] To a solution of 2-(2,5-dimethoxy-4-pyridyl)azepane-1-carbaldehyde, 86, (1.00 g, 3.78 mmol) in THF (20 mL) was added n-butyllithium (5.0 mL 1.6 M, 8.00 mmol) at -78°C. The mixture was stirred at -78°C for 2 hours. The reaction mixture was carefully quenched by the addition of MeOH. 2N HCl solution was added to the mixture until pH = 2 was reached. The resulting solution was then basified by the addition of 6N NaOH until pH = 10 was reached. The aqueous solution was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to give 230 mg of the desired product: ESI-MS m / z calculated 236.15, found 237.15 (M+1) + ; Retention time: 0.58 minutes.

[0925] Formation of 4-[2-(2,5-dimethoxy-4-pyridinyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (88) I-116

[0926] To the mixture of solid 4-chloro-6-methyl-pyrimidine-2-amine (0.12 g, 0.81 mmol) and 2-(2,5-dimethoxy-4-pyridyl)azepane (0.23 g, 0.90 mmol) in the bottle was added EtOH (2 mL). The bottle was placed on a hot plate and heated at 160 ° C for 2 hours without a cover. The crude solid was purified by silica gel chromatography (40 g) in ISCO, eluting with 20% MeOH / dichloromethane-dichloromethane to obtain 6.5 mg of the desired product: 1 H NMR (300 MHz, DMSO-d6) 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 calculated 343.20, found 344.16 (M+1) + ; Retention time: 0.65 minutes.

[0927] The following analogs were prepared according to Synthetic Scheme 10:

[0928]

[0929] 4-[2-(2-Chloro-5-isopropoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (89) I-104

[0930] 1 H NMR (300 MHz, DMSO-d6) 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 calculated 374.19, found 375.07 (M+1) + ; Retention time: 0.76 minutes.

[0931]

[0932] (R)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (90) I-108

[0933] SFC conditions: column: IC, 4.6x100 mm IC, 20x250 mm; mobile phase: 40% EtOH (5 mM ammonia), 60% CO2.

[0934] Peak A: [α] D (c=0.5, MeOH)+58.56; 99% ee; (R)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (90): 1 H NMR (300 MHz, DMSO-d6) 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 calculated 374.19, found 375.07 (M+1) + ; Retention time: 0.75 minutes. I-108

[0935] Peak B: [α] D (c=0.5, MeOH)-70.52; 98.4% ee; (S)-4-[2-(2-chloro-5-isopropoxy-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (91): 1 H NMR (300 MHz, DMSO-d6) 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 calculated 374.19, found 375.12 (M+1) + ; Retention time: 0.77 minutes. I-109

[0936]

[0937] 3-[1-(2-Amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (92) I-107

[0938] 1 H NMR (300 MHz, DMSO-d6) 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 calculated 328.19, found 329.17 (M+1) + ; Retention time: 0.67 minutes.

[0939]

[0940] (R)-3-[1-(2-amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (93) I-127

[0941] SFC conditions: column: IC, 4.6x100 mm IC, 20x250 mm; mobile phase: 30% MeOH (5 mM ammonia), 70% CO2.

[0942] Peak A: [α] D (c=0.5,MeOH)+100.16; 87.6%ee

[0943] 3-[1-(2-Amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (93): 1 HNMR (300 MHz, DMSO-d6) 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 calculated 328.19, found 329.25 (M+1) + ; Retention time: 0.65 minutes. I-127

[0944] Peak B: [α] D(c=0.5,MeOH)-98.32; 94%ee

[0945] 3-[1-(2-Amino-6-methyl-pyrimidin-4-yl)azepan-2-yl]-4-methoxy-phenol (94): 1 HNMR (300 MHz, DMSO-d6) 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 calculated 328.19, found 329.1 (M+1) + ; Retention time: 0.65 minutes. I-128

[0946]

[0947] (±)-4-methyl-6-(2-(2-methylpyridin-3-yl)azepan-1-yl)pyrimidin-2-amine (95) I-24

[0948] 1 H NMR (400 MHz, DMSO- d 6) δ 8.30 (d, J = 4.6 Hz, 1H), 7.42 (d, J = 7.9 Hz, 1H), 7.12 (dd, J = 7.8, 4.7 Hz, 1H), 6.94 (s, 2H), 6.18-6.00 (m, 1H), 5.38 (s, 1H), 4.29 (s, 2H), 3.63 (s, 1H), 2.63 (s, 3H), 2.32-2.22 (m, 1H), 2.21 (s, 3H), 2.00-1.73 (m, 3H), 1.56-1.28 (m, 4H); ESI-MS m / z calculated 297.2, found 298.2 (M+1) + ; Retention time: 0.49 minutes.

[0949]

[0950] 4-(2-(2-Fluorophenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (96) I-36

[0951] 1H NMR (300 MHz, DMSO-d6) δ 7.28 (m, 2H), 7.20-7.06 (m, 3H), 6.30 (s, 2H), 6.20-5.62 (m, 1H), 3.48-3.07 (m, 2H), 2.10 (brs, 3H), 1.98-1.18 (m, 8H); ESI-MS m / z calculated 300.2, found 301.2 (M+1) + ; Retention time: 0.7 minutes.

[0952]

[0953] 4-(2-(5-chloro-2-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine I-21

[0954] 1 H NMR (300 MHz, DMSO-d6) δ 7.46 (brs, 1H), 7.37-7.23 (m, 2H), 7.17-6.96 (m, 2H), 6.87 (s, 0.5H), 6.43 (s, 0.5H), 5.84-5.59 (m, 1H), 4.96 (d, J = 10.2 Hz, 1H), 4.06 (d, J = 15.4 Hz, 1H), 3.88 (d, J = 15.1 Hz, 3H), 3.55 (dt, J = 42.6, 12.7 Hz, 1H), 2.20 (d, J = 38.7 Hz, 3H), 2.01-1.03 (m, 8H); ESI-MS m / z calculated 346.16, found 347.23 (M+1) + ; Retention time: 0.73 minutes.

[0955]

[0956] 4-(2-(4-chloro-2-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine I-20

[0957] 1 H NMR (300 MHz, DMSO-d6) δ 7.44-6.85 (m, 6H), 6.39 (s, 0.5H), 5.62 (s, 0.5H), 4.81 (dd, J = 71.0, 12.5 Hz, 1H), 4.18-3.80 (m, 4H), 3.68-3.23 (m, 4H), 2.18 (d, J = 39.0 Hz, 4H), 2.01-1.07 (m, 7H); ESI-MS m / z calculated 346.16, found 347.23 (M+1) + ; Retention time: 0.74 minutes.

[0958]

[0959] 4-(2-(4-fluoro-2-methoxyphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine I-22

[0960] 1 H NMR (400 MHz, DMSO-d6) δ 6.98 (dd, J = 8.4, 6.9 Hz, 1H), 6.84 (dd, J = 11.2, 2.5 Hz, 1H), 6.61 (td, J = 8.5, 2.5 Hz, 1H), 5.56 (s, 1H), 5.35 (s, 2H), 5.14 (s, 1H), 4.38 (s, 1H), 3.36-3.26 (m, 1H), 2.39-2.29 (m, 1H), 1.98 (s, 3H), 1.81 (d, J = 47.9 Hz, 3H), 1.69-1.44 (m, 2H), 1.40-1.18 (m, 2H); ESI-MS m / z calculated 330.2, found 331.2 (M+1) + ; Retention time: 0.67 minutes.

[0961] Example 11

[0962] Synthesis Scheme 11: (±)-4-(2-(2-methoxy-4-(methylsulfonyl)phenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (100) I-88

[0963]

[0964] (a) 1-Bromo-2-methoxy-4-methylsulfonyl-benzene, bis(pinocalatodiboron), PdCl2(Ph3P)2, KOAc, di Alkane, water, 85°C; (b) (c) Pd / C, formic acid, EtOAc, MeOH; (d) nBuLi, THF, -78°C; (e) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (f) SFC chiral separation

[0965] Formation of 7-(2-methoxy-4-methylsulfonyl-phenyl)-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde (97)

[0966] Step-1: To 1-bromo-2-methoxy-4-methylsulfonyl-benzene (1.00 g, 3.77 mmol) in dibromo- To a solution of bis(pentanoyl)boron (1.44 g, 5.66 mmol) and potassium acetate (1.11 g, 11.32 mmol) in oxane (50 mL) was added. The mixture was purged with nitrogen for 15 minutes and dichloro-bis(triphenylphosphorane)-palladium (0.27 g, 0.37 mmol) was added. The reaction was heated to 85°C for 18 hours. The mixture was diluted with EtOAc and filtered through celite, washing with EtOAc (60 mL). The organic phase was concentrated in vacuo. The resulting dark brown solid was used without further purification.

[0967] Step-2: The above crude product was dissolved in DME (30 mL). 7-Chloro-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde, 73, (0.60 g, 3.77 mmol) was added, followed by NaHCO (6.3 mL of a 1.2 M solution, 7.54 mmol). The mixture was sparged with nitrogen and a Pd(dppf)Cl catalyst was added. The flask was capped and heated at 80° C. for 12 hours. The residue was purified by silica gel chromatography using a 20% MeOH-dichloromethane / dichloromethane gradient (40 g ISCO column). The desired fractions were collected and evaporated. The fractions were collected and used directly in the next step.

[0968] Formation of 2-(2-methoxy-4-methylsulfonyl-phenyl)azepane-1-carbaldehyde (98)

[0969] To a solution of 7-(2-methoxy-4-methylsulfonyl-phenyl)-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde, 97, (1.00 g, 3.23 mmol) in MeOH (10 mL) and EtOAc (10 mL) was added acetic acid (1 mL). Under a nitrogen atmosphere, 10% Pd / C (10 mol%) was added. The reaction mixture was purged with hydrogen 3 times and then stirred under a hydrogen atmosphere for 14 hours. LCMS indicated poor conversion to the desired product. The mixture was filtered through diatomaceous earth and the solvent was partially concentrated in vacuo. The above operation was repeated, but acetic acid was replaced by formic acid. After stirring overnight, the starting material was converted into the desired product. The mixture was filtered through diatomaceous earth and the filtrate was concentrated in vacuo. The obtained residue was purified by silica gel chromatography (40 g ISCO column) eluted with EtOAc / heptanes (0-75%) gradient to obtain 760 mg of the desired product: 1H NMR(300MHz, CDCl3)δ8.20(s,s,1H),7.63-7.38(m,2H),7.35-7.16(m,1H), 5.41(dd,J=12.3,4.7Hz,0.6H),5.00(dd,J=11.7,5.6Hz,0.4H),4.35(d,J= 13.7Hz,0.4H),3.96(s,3H),3.91-3.79(m,0.6H),3.56(dd,J=14.9,11.3Hz ,0.6H),3.06(s,3H),3.01-2.85(m,0.4H),2.46(m,1H),2.19-1.17(m,7H).

[0970] Formation of 2-(2-methoxy-4-methylsulfonyl-phenyl)azepane (99)

[0971] To a solution of 2-(2-methoxy-4-methylsulfonyl-phenyl)azepane-1-carbaldehyde, 98, (0.76 g, 2.44 mmol) in MeOH (20 mL) was added HCl (10 mL 12M, 120 mmol). The mixture was heated at 100° C. for 4 hours. The solvent was concentrated in vacuo to give 600 mg of the desired product, which was used without further purification: 1 H NMR (300 MHz, DMSO-d6) δ 9.49 (br, 2H), 7.82 (d, J = 8.0 Hz, 1H), 7.65-7.48 (m, 2H), 4.59 (t, J = 9.2 Hz, 1H), 3.97 (s, 3H), 3.27 (s, 3H), 3.19-3.08 (m, 2H), 2.34-1.51 (m, 8H); ESI-MS m / z calculated 283.12, found 284.27 (M+1) + ; Retention time: 0.56 minutes.

[0972] Formation of (±)-4-[2-(2-methoxy-4-methylsulfonyl-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (100) I-88

[0973] To a mixture of solid 4-chloro-6-methyl-pyrimidin-2-amine (0.10 g, 0.68 mmol) and 2-(2-methoxy-4-methylsulfonyl-phenyl)azepane-HCl, 99, (0.25 g, 0.78 mmol) in a bottle was added EtOH (2 mL). The bottle was placed on a hot plate and heated at 170 ° C for 2 hours without a cap. The crude solid was purified by silica gel chromatography (40 g ISCO column) eluting with 20% MeOH-dichloromethane / dichloromethane to give 182 mg of the desired product:1 H NMR (300 MHz, DMSO-d6) δ 7.59-7.38 (m, 2H), 7.22 (s, 1H), 6.06-5.23 (m, 3H), 4.82 (brs, 1H), 4.00 (s, 3H), 3.31 (brs, 2H), 3.22 (s, 3H), 1.94 (s, 3H), 1.87-1.01 (m, 8H); ESI-MS m / z calculated 390.17, found 391.09 (M+1) + ; Retention time: 0.66 minutes.

[0974] The racemic mixture (182 mg) was subjected to SFC chiral separation.

[0975] SFC conditions: Column: AD-H, 4.6x100 mm AD-H, 10x250 mm; Mobile phase: 40% EtOH (5 mM ammonia), 60% CO2

[0976] I-98 Peak A: [α] D (c=0.5, MeOH)-72.39; ee=99%

[0977] 4-[2-(2-Methoxy-4-methylsulfonyl-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (101): 1 H NMR (400 MHz, DMSO-d6) δ 7.59-7.40 (m, 2H), 7.26 (d, J = 8.0 Hz, 1H), 5.64 (s, 1H), 5.40 (br, 2H), 4.39 (brs, 1H), 4.01 (s, 3H), 3.57-3.34 (m, 1H), 3.17 (s, 3H), 2.48-2.29 (m, 1H), 2.03 (s, 3H), 1.93-1.04 (m, 8H). ESI-MS m / z calculated 390.17, found 391.09 (M+1) + ; Retention time: 0.67 minutes.

[0978] I-99 Peak B:[α] D (c=0.5, MeOH)+86.51; ee=99.6%

[0979] 4-[2-(2-Methoxy-4-methylsulfonyl-phenyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (102): 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, J = 1.6 Hz, 1H), 7.36-7.26 (m, 1H), 7.16 (d, J = 7.9 Hz, 1H), 5.54 (s, 1H), 5.30 (s, 2H), 4.28 (brs, 1H), 3.92 (s, 3H), 3.35-3.20 (m, 1H), 3.07 (s, 3H), 2.40-2.26 (m, 1H), 1.93 (s, 3H), 1.87-1.10 (m, 8H); ESI-MS m / z calculated 390.17, found 391.05 (M+1) + ; Retention time: 0.66 minutes.

[0980] The following analogs were prepared according to Synthetic Scheme 11:

[0981]

[0982] (±)-4-[2-(3-methoxy-4-pyridinyl)azepan-1-yl]-6-methyl-pyrimidin-2-amine (103) I-80

[0983] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 5.9 Hz, 1H), 8.34 (d, J = 5.3 Hz, 1H), 7.62 (s, 2H), 7.36 (d, J = 5.3 Hz, 1H), 6.52 (s, 1H), 5.69 (m, 1H), 4.06 (s, 3H), 3.78-3.37 (m, 2H), 2.28 (s, 3H), 2.03-1.14 (m, 8H); ESI-MS m / z calculated 313.19, found 314.14 (M+1) + ; Retention time: 0.56 minutes.

[0984]

[0985] (±)-4-(2-(2-methoxypyridin-3-yl)azepan-1-yl)-6-methylpyrimidin-2-amine I-18

[0986] 1H NMR(400MHz,DMSO-d6)δ8.00(dd,J=4.9,1.8Hz,1H),7.34(dd,J=7.2,1.6Hz,1 H),6.86(dd,J=7.3,4.9Hz,1H),5.61(s,1H),5.36(s,2H),5.19(s,1H),4.32( s,1H),3.96(s,3H),3.37-3.28(m,1H),2.96(s,5H),2.45-2.35(m,1H),2.00( s,3H),1.88(s,1H),1.75(s,2H),1.70-1.44(m,3H),1.41-1.20(m,2H); ESI-MS m / z calculated 313.2, found 314.2 (M+1) + ; Retention time: 0.61 minutes.

[0987] Example 12

[0988] Synthesis Scheme 12: (±)-4-(2-(2-ethylphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (107) I-45

[0989]

[0990] (a) (2-Ethylphenyl)boronic acid, PdCl2(dppf), NaHCO3, DMF, water, 85°C; (b) Pd / C, formic acid, EtOAc, MeOH; (c) nBuLi, THF, -78°C; (d) 2-amino-4-chloro-6-methylpyrimidine, NMP, 150°C; (e) SFC chiral separation

[0991] Formation of 7-(2-ethylphenyl)-2,3,4,5-tetrahydro-1H-azacycloheptatriene-1-carbaldehyde (104)

[0992] A mixture of 7-chloro-2,3,4,5-tetrahydroazacycloheptatriene-1-carbaldehyde, 73, (1.5 g, 9.4 mmol), (2-ethylphenyl)boronic acid (1.4 g, 9.4 mmol) and PdCl2(dppf) (0.4 g, 0.5 mmol) in DMF (30 mL) and saturated NaHCO3 aqueous solution (10 mL) was heated at 80°C with microwave irradiation for 30 minutes. The mixture was filtered through celite, diluted with EtOAc, and washed with water. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluting with 0-50% EtOAc / heptane. The pure fractions were combined and concentrated to give 1.68 g of the desired product as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.29 (ddd, J = 7.7, 6.3, 2.2 Hz, 1H), 7.23-7.14 (m, 3H), 5.39 (t, J = 5.7 Hz, 1H), 3.96-3.87 (m, 2H), 2.57 (q, J = 7.5 Hz, 2H), 2.39-2.32 (m, 2H), 1.92 (tt, J = 6.2, 5.2 Hz, 2H), 1.84-1.74 (m, 2H), 1.20 (t, J = 7.6 Hz, 3H); ESI-MS m / z calculated 229.1, found 230.0 (M+1) + ; Retention time: 1.05 minutes.

[0993] Formation of (±)-2-(2-ethylphenyl)azepane-1-carbaldehyde (105)

[0994] A mixture of 7-(2-ethylphenyl)-2,3,4,5-tetrahydro-1H-azacycloheptatriene-1-carbaldehyde, 104, (1.68 g, 7.33 mmol) and wet Pd / C (0.79 g, 0.37 mmol) in ethyl acetate (25 mL) and MeOH (25 mL) was shaken overnight under 55 psi of hydrogen. The reaction mixture was filtered through celite and the filter pad was rinsed with EtOAc. The filtrate was dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1.47 g of a light yellow oil: 1 H NMR (400 MHz, DMSO-d6) δ 8.06 (d, J = 55.7 Hz, 1H), 7.22-7.05 (m, 4H), 5.04 (ddd, J = 106.0, 12.0, 4.9 Hz, 1H), 4.13-4.00 (m, 0.5H), 3.90-3.78 (m, 1H), 3.63-3.50 (m, 1H), 3.25-3.15 (m, 0.5H), 2.84-2.63 (m, 2H), 2.22-1.66 (m, 5H), 1.49-1.11 (m, 6H); ESI-MS m / z calculated 231.2, found 232.0 (M+1) + ; Retention time: 1.03 minutes.

[0995] Formation of (±)-2-(2-ethylphenyl)azepane (106)

[0996] A solution of 2-(2-ethylphenyl)azepane-1-carbaldehyde, 105, (1.47 g, 6.35 mmol) in MeOH (5 mL) and concentrated HCl (5 mL of a 12.1 M solution, 60.50 mmol) was refluxed overnight. The resulting mixture was concentrated to dryness, dissolved in a minimum amount of MeOH and added dropwise to cold ether with vigorous stirring. The resulting white precipitate was filtered and dried to give 1.15 g of the desired product as the HCl salt: 1 H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 9.26 (s, 1H), 7.76-7.61 (m, 1H), 7.41-7.18 (m, 3H), 4.43 (d, J = 10.6 Hz, 1H), 3.42-3.02 (m, 2H), 2.72 (ddt, J = 19.3, 14.6, 7.3 Hz, 2H), 2.33-1.45 (m, 6H), 1.16 (t, J = 7.5 Hz, 3H); ESI-MS m / z calculated 203.2, found 204.0 (M+1) + ; Retention time: 0.67 minutes.

[0997] Formation of (±)-4-(2-(2-ethylphenyl)azepan-1-yl)-6-methylpyrimidin-2-amine (107) I-45

[0998] A mixture of 2-(2-ethylphenyl)azepane-HCl, 106, (0.15 g, 0.63 mmol), 4-chloro-6-methyl-pyrimidin-2-amine (0.09 g, 0.63 mmol) and triethylamine (0.17 mL, 1.25 mmol) in NMP (2 mL) was stirred at 150° C. for 5 hours in a sealed tube. The crude reaction mixture was purified by reverse phase silica gel chromatography.

[0999] The product was purified by direct injection onto a 50 g C18 aqueous ISCO column and eluted with 5-50% MeCN in water (containing 0.1% TFA). Pure fractions were combined, neutralized with saturated sodium bicarbonate, and extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered, concentrated in vacuo, and freeze-dried to give 45 mg of the desired product: 1H NMR(400MHz,DMSO-d6)δ7.18(d,J=7.5Hz,1H),7.15-7.09(m,1H),7.09-7.04(m,2H ),5.67(s,1H),5.54(s,2H),5.27(s,1H),4.33(d,J=14.8Hz,1H),3.54-3.40(m,1H ), 2.88-2.69 (m, 2H), 2.16 (ddd, J = 14.2, 8.2, 5.1 Hz, 1H), 2.01 (s, 3H), 1.96-1.67 (m, 3H), 1.52 (q, J = 12.9, 12.4 Hz, 1H), 1.46-1.33 (m, 2H), 1.33-1.24 (m, 4H); ESI-MS m / z calculated 310.2, found 311.0 (M+1) + ; Retention time: 0.84 minutes.

[1000] The following analogs were prepared according to Synthetic Scheme 12:

[1001]

[1002] 3-(1-(2-amino-6-methylpyrimidin-4-yl)azepan-2-yl)-4-fluoro-N-methylbenzamide (108) I-55

[1003] 1 H NMR(400MHz, DMSO-d6)δ8.14-8.06(m,1H),7.71(ddd,J=8.5,5.0,2.3Hz,1H),7.62(d d,J=7.4,2.3Hz,1H),7.19-7.13(m,1H),5.80(s,1H),5.68(s,2H),5.41(d,J=35.0Hz, 1H), 4.25 (m, 1H), 3.49-3.42 (m, 1H), 2.76 (d, J = 4.5 Hz, 3H), 2.32 (dt, J = 14.3, 7.1 Hz, 1H), 2.06 (s, 3H), 1.95-1.69 (m, 4H), 1.55 (p, J = 11.5 Hz, 1H), 1.45-1.22 (m, 2H); ESI-MS m / z calculated 357.2, found 358.0 (M+1) + ; Retention time: 0.67 minutes.

[1004] Example 13

[1005] Synthesis Scheme 13: (±)-3-[4-(2-amino-6-methyl-pyrimidin-4-yl)-1,4-oxazepan-3-yl]-4-chloro-phenol (112) I-147

[1006]

[1007] (a) 2,5-Dimethoxyphenylboronic acid, Pd(Ph3P)2Cl2, DME, 50°C; (b) nBuLi, THF, -78°C; (c) NaBH4, MeOH; (d) 2-Amino-4-chloro-6-methylpyrimidine, EtOH, 160°C; (e) SFC chiral separation

[1008] Formation of 3-chloro-6,7-dihydro-1,4-oxazepine-4(5H)-carbaldehyde (109)

[1009] Intermediate 109 was prepared according to Scheme 9 using 1,4-oxazepan-3-one instead of azepan-2-one.

[1010] Formation of 3-(2-chloro-5-hydroxyphenyl)-6,7-dihydro-1,4-oxazepine-4(5H)-carbaldehyde (110)

[1011] Under nitrogen, a 2-neck rb flask was charged with 3-chloro-6,7-dihydro-5H-1,4-oxazepine-4-carboxaldehyde, 109, (0.46 g, 2.80 mmol), NaHCO3 (6.0 mL 1.2 M solution, 7.2 mmol) and (2-chloro-5-hydroxy-phenyl)boronic acid (0.50 g, 2.90 mmol) in dimethoxyethane (10 mL). Bis(triphenylphosphine)palladium(II) chloride (0.10 g, 0.14 mmol) was then added and the reaction mixture was heated at 60 ° C overnight. The mixture was diluted with water and dichloromethane. The layers were separated by a phase separator and the organic matter was concentrated in vacuo after the second extraction. Purification by silica gel chromatography (40 g GOLD column; 10-100% EtOAc / heptane gradient) gave 650 mg of the desired product: 1 H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H), 7.28 (s, 0H), 7.20 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 2.7 Hz, 1H), 6.13 (s, 1H), 4.25 (t, J = 5.8 Hz, 2H), 4.11 (t, J = 6.3 Hz, 3H), 2.15 (t, J = 6.2 Hz, 2H); ESI-MS m / z calculated 253.05, found 252.29 (M+1) + ; Retention time: 0.55 minutes.

[1012] Formation of (±)-4-chloro-3-(1,4-oxazepan-3-yl)phenol (111)

[1013] To a cold (-78°C) solution of 3-(2-chloro-5-hydroxy-phenyl)-6,7-dihydro-5H-1,4-oxazepine-4-carbaldehyde, 110, (0.65 g, 1.55 mmol) in THF (10 mL) was added n-butyllithium (3 mL of a 1.6 M solution, 4.80 mmol). The mixture was stirred at this temperature for 50 minutes. The reaction mixture was carefully quenched by the addition of methanol. More MeOH (30 mL) was added and the solution was warmed to room temperature. The resulting solution was used directly in the next step; ESI-MS m / z calculated 225.06, found 226.08 (M+1) + ; Retention time: 0.54 minutes.

[1014] To the above solution was added NaBH4 (0.09 g, 2.38 mmol). The mixture was stirred at room temperature overnight. The reaction was quenched by the addition of MeOH and then 2N HCl solution. The acidic solution was then basified with 6N NaOH, and the aqueous phase was extracted three times with EtOAc. The combined organic phases were washed with brine, dried over MgSO4, filtered and evaporated. The crude product (300 mg, 77%) was obtained and used directly; ESI-MS m / z calculated 227.07, found 228.09 (M+1) + ; Retention time: 0.54 minutes.

[1015] Formation of (±)-3-(4-(2-amino-6-methylpyrimidin-4-yl)-1,4-oxazepan-3-yl)-4-chlorophenol (112)I-147

[1016] To a mixture of solid 4-chloro-6-methyl-pyrimidin-2-amine (0.30 g, 2.04 mmol) and 4-chloro-3-(1,4-oxazepan-3-yl)phenol, 111, (1.43 g, 2.22 mmol) in a bottle was added EtOH (2 mL). The bottle was placed on a hot plate and heated at 160 ° C for 2 hours without a cap. The crude solid was purified by a silica gel column (40 g) in ISCO, eluting with a 20% MeOH-DCM / DCM gradient (0% B to 50% B) to give 192 mg of the desired product: 1H NMR (300 MHz, DMSO-d6) δ 9.80 (s, 1H), 7.72 (brs, 1H), 7.48-7.18 (m, 2H), 6.90-6.54 (m, 2.5H), 5.93 (br, 0.5H), 5.59 (s, 0.5H), 5.26-5.07 (m, 0.5H), 4.99 (m, 0.5H), 4.43-4.04 (m, 1.5H), 3.86 (m, 3H), 3.62 (t, J = 10.2 Hz, 1H), 2.18 (s, 3H), 1.84 (m, 2H); ESI-MS m / z calculated 334.12, found 335.10 (M+1) + Retention time: 0.6 min. The racemic mixture (180 mg) was purified by chiral SFC to yield the individual enantiomers. SFC conditions: Column: Cellulose-2, 20 x 250 mm; Mobile phase: 30% EtOH (5 mM ammonia), 70% CO2; Flow rate: 80 mL / min; Concentration: ~18 mg / mL (MeOH); Injection volume: 250 μL; Wavelength: 220 nm.

[1017] (I-169) Peak A: 96.8...

Claims

1. Compounds of Formula I' or a pharmaceutically acceptable salt thereof, wherein: Ring A is a ring selected from the following: phenyl, 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; Each R 1 is independently hydrogen or C optionally substituted by 1-6 halogens 1-3 an aliphatic group; or Two R's 1 The groups optionally form together with their intervening atoms a 5-8 membered partially unsaturated fused carbocyclic ring; Each R 2 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 R's 2 The groups are optionally taken together to form =0; or Two R's 2 The groups optionally form, together with their intervening atoms, a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; Each R 3 are independently hydrogen, -OH or C 1-3 an aliphatic group; or Two R's 3 The groups are optionally taken together to form =0; or Two R's 3 The groups are optionally taken together to form =CH2; or Two R's 3 The groups optionally form, together with their intervening atoms, a 3-8 membered saturated spirocyclic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen or sulfur; or Two R's 3 The groups are optionally taken together with their intervening atoms to form a 5-8 membered saturated bridged 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 the following: C 1-6 aliphatic, a 3-8 membered saturated or partially unsaturated monocyclic carbocyclic ring, phenyl, a 7-10 membered saturated spiro bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, a 7-10 membered saturated or partially unsaturated fused 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 optionally form together with their intervening atoms a 4-7 membered saturated, partially unsaturated or heteroaryl ring having, in addition to the nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur, optionally substituted with 1-2 oxo groups; is a single bond or a double bond; X is -O-, -S- or -CH2-; m is 0, 1, or 2; n is 0, 1, 2, 3, 4 or 5; and p is 0, 1 or 2.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring A is phenyl.

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is an 8-12 membered saturated or partially unsaturated bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is an 8-10 membered bicyclic heteroaromatic ring having 1-5 heteroatoms independently selected from nitrogen, oxygen or sulfur.

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is wherein 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.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from:

7. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 At least one of them is C 1-3 Aliphatic group.

8. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 At least one of them is -CH3.

9. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 1 At least one of them is connected to position 6 of the pyrimidine.

10. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is C 1-6 Aliphatic group, which is 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.

11. The compound according to claim 10, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of -CH3, -CF3, -CH2CH3, -C≡CH, 12. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of the rings is a 3-6 membered saturated monocyclic carbocyclic ring.

13. The compound according to claim 12, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 14. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of the is a 7-10 membered saturated spiro bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen.

15. The compound according to claim 14, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 16. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of is a 7-10 membered saturated fused bicyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen.

17. The compound according to claim 16, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 18. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of is a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted by halogen, -OH, -CH3, -OCH3, =O, Replace 1-4 times.

19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 20. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of is a 5-6 membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur.

21. The compound according to claim 20, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 22. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -C(O)OR, wherein R is hydrogen or C 1-6 Aliphatic group.

23. The compound according to claim 22, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -C(O)OH, 24. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -C(O)NR2, wherein each R is independently hydrogen, C optionally substituted with -N(CH3)2 1-6 an aliphatic group, an unsubstituted 3-6 membered saturated monocyclic carbocyclic ring, or an unsubstituted 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen, or two R together with their intervening atoms form a 4-7 membered saturated and unsubstituted ring having, in addition to nitrogen, 0-3 heteroatoms independently selected from nitrogen, oxygen and sulfur.

25. The compound according to claim 24, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 26. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -NR2, wherein each R is independently: hydrogen; C 1-6 aliphatic group, which is optionally substituted with -OH, Replace 1-2 times; Unsubstituted 3-6 membered saturated monocyclic carbocyclic ring; A 4-6 membered saturated monocyclic heterocycle 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 A 6-membered monocyclic heteroaromatic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, which is optionally substituted 1-2 times with -CH3 or -NH2.

27. The compound according to claim 26, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one selected from:

28. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -NHC(O)R, wherein R is C optionally substituted 1-3 times by halogen, -OCH3, -N(CH3)2 or -OH 1-6 aliphatic, a 3-6 membered saturated monocyclic carbocyclic ring optionally substituted 1-2 times by halogen or -OH, or a 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen or sulfur, optionally substituted 1-2 times by halogen, -OH or -CH3.

29. The compound according to claim 28, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 30. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -NHC(O)OR, wherein R is an unsubstituted C 1-6 Aliphatic group.

31. The compound according to claim 30, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 32. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -NHS(O)2R, wherein R is an unsubstituted C 1-6 Aliphatic group.

33. The compound according to claim 32, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 34. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of is -OR, where R is: hydrogen; C 1-6 aliphatic groups, which are optionally substituted with halogen, -OH, -C(O)NHC 1-4 Aliphatic group, -COOH, -C(O)OC 1-4 Aliphatic group, -CN, -SO2C 1-4 Aliphatic or replace; or A 4-6 membered saturated monocyclic heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen or oxygen.

35. The compound according to claim 34, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of -OH, -O-CH2-C≡CH, 36. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -P(O)R2, wherein each R is independently an unsubstituted C 1-6 Aliphatic group.

37. The compound according to claim 36, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 38. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -SR, wherein R is an unsubstituted C 1-6 Aliphatic group.

39. The compound according to claim 38, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 40. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -S(O)R, wherein R is an unsubstituted C 1-6 Aliphatic group.

41. The compound according to claim 39, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 42. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -S(O)2R, wherein R is an unsubstituted C 1-6 An aliphatic group or a 3-6 membered saturated monocyclic carbon ring.

43. The compound according to claim 42, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 44. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -S(O)(NH)R, wherein R is an unsubstituted C 1-6 Aliphatic group.

45. The compound according to claim 44, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of 46. ​​The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -S(O)2NR2.

47. The compound according to claim 46, or a pharmaceutically acceptable salt thereof, wherein R 2 At least one of them is -S(O)2NH2.

48. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 3 At least one of them is C 1-3 Aliphatic group.

49. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein X is -O-.

50. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1.

51. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein p is 0.

52. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, 3, 4 or 5.

53. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein It is a single bond.

54. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula VII or a pharmaceutically acceptable salt thereof, wherein: n' is 1 or 2; and R 2’ Is halogen or -OC 1-3 Aliphatic group.

55. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of Formula VIII or a pharmaceutically acceptable salt thereof, wherein: 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; n” is 0, 1, 2, 3 or 4; and R 2’ Is halogen or -OC 1-3 Aliphatic group.

56. The compound according to claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein R 2’ It's a halogen.

57. The compound according to claim 56, or a pharmaceutically acceptable salt thereof, wherein R 2’ It is Cl.

58. The compound according to claim 54 or 55, or a pharmaceutically acceptable salt thereof, wherein R 2’ It is -OCH3.

59. According to claim 54, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula VII-a and R 2’ It is Cl.

60. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is of formula XI or XI-a, And R 2’ It's a halogen.

61. According to claim 60, or a pharmaceutically acceptable salt thereof, wherein R 2’ is Cl; and R 2 Selected from Cl,-NH2,-CH3,-CF3, -CH2CH3, =O,-OH,-COOH, -S(O)2NH2,-OCHF2,-OCF3,-C≡CH,-O-CH2-C≡CH, and 62. A compound selected from: or a pharmaceutically acceptable salt thereof.

63. According to claim 62, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the following compounds 64. The compound according to claim 63, or a pharmaceutically acceptable salt thereof, wherein the compound is 65. A pharmaceutical composition comprising a compound according to any one of claims 1-55, 57 and 59-64 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, adjuvant or vehicle.

66. Use of a compound according to any one of claims 1-64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for treating a cell proliferative disorder in a patient, comprising administering the medicament to the patient, wherein the cell proliferative disorder is selected from astrocytoma, bile duct cancer, bladder cancer, brain cancer, breast cancer, cervical cancer, colorectal cancer, esophageal cancer, germ cell cancer, glioblastoma, glioma, head and neck cancer, kidney cancer, leukemia, liver cancer, lung cancer, lymphoma, mesothelioma, multiple myeloma, neuroblastoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, skin cancer, thyroid cancer and uterine cancer.

67. The use according to claim 66, further comprising determining the expression level of Wolframin (WFS1).

68. Use of a compound according to any one of claims 1-64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for inducing ER stress in a patient in need thereof, comprising administering the medicament to the patient.

69. Use of a compound according to any one of claims 1-64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for inducing an unfolded protein response (UPR) in a patient in need thereof, comprising administering the medicament to the patient.

70. Use of a compound according to any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for the preparation of a medicament for the treatment of a patient in need thereof via a putative Ca2+-dependent molecule known as Wolframin (WFS1). 2+ The channel causes calcium release from the endoplasmic reticulum (ER), comprising administering the drug to the patient.

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