FIELD OF THE INVENTION

The present invention relates to substituted heteroaryl derivatives that are inhibitors of the ATF4 pathway. The present invention also relates to pharmaceutical compositions comprising such compounds and methods of using such compounds in the treatment of diseases/injuries associated with activated unfolded protein response pathways, such as cancer, pre-cancerous syndromes, Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.

BACKGROUND OF THE INVENTION

In metazoa, diverse stress signals converge at a single phosphorylation event at serine 51 of a common effector, the translation initiation factor elF2a. This step is carried out by four elF2a kinases in mammalian cells: PERK, which responds to an accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 to amino acid starvation and UV light, PKR to viral infection, and HRI to heme deficiency. This collection of signaling pathways has been termed the "integrated stress response"

(ISR), as they converge on the same molecular event. elF2a phosphorylation results in an attenuation of translation with consequences that allow cells to cope with the varied stresses (1). elF2 (which is comprised of three subunits, a, b , a n d y) binds GTP and the initiator Met-tRNA to form the ternary complex (elF2-GTP-Met-tRNAi), which, in turn, associates with the 40S ribosomal subunit scanning the 5'UTR ofmRNAs to select the initiating AUG codon. Upon phosphorylation of its a-subunit, elF2 becomes a competitive inhibitor of its GTP-exchange factor (GEF), elF2B (2). The tight and nonproductive binding of phosphorylated elF2 to elF2B prevents loading of the elF2 complex with GTP thus blocking ternary complex formation and reducing translation initiation (3). Because elF2B is less abundant than elF2, phosphorylation of only a small fraction of the total elF2 has a dramatic impact on elF2B activity in cells.

Paradoxically, under conditions of reduced protein synthesis, a small group of mRNAs that contain upstream open reading frames (uORFs) in their 5'UTR are translationally up-regulated (4,5). These include mammalian ATF4 (a cAMP element binding (CREB) transcription factor) and CHOP (a pro-apoptotic transcription factor) (6- 8). ATF4 regulates the expression of many genes involved in metabolism and nutrient uptake and additional transcription factors, such as CHOP, which is under both translational and transcriptional control (9). Phosphorylation of elF2a thus leads to preferential translation of key regulatory molecules and directs diverse changes in the transcriptome of cells upon cellular stress.

One of the elF2a kinases, PERK, lies at the intersection of the ISR and the unfolded protein response (UPR) that maintains homeostasis of protein folding rates in the ER (10). The UPR is activated by unfolded or misfolded proteins that accumulate in the ER lumen because of an imbalance between protein folding load and protein folding capacity, a condition known as "ER stress". In mammals, the UPR is comprised of three signaling branches mediated by ER- localized transmembrane sensors, PERK, IRE1 , and ATF6. These sensor proteins detect the accumulation of unfolded protein in the ER and transmit the information across the ER membrane, initiating unique signaling pathways that converge in the activation of an extensive transcriptional response, which ultimately results in ER expansion (11). The lumenal stress-sensing domains of PERK and IRE1 are homologous and likely activated in analogous ways by direct binding to unfolded peptides (12). This binding event leads to oligomerization and trans- autophosphorylation of their cytosolic kinase domains, and, for PERK, phosphorylation of its only known substrate, elF2a. In this way, PERK activation results in a quick reduction in the load of newly synthesized proteins that are translocated into the ER- lumen (13).

Upon ER stress, both the transcription factor XBP1 s, produced as the consequence of a non-conventional mRNA splicing reaction initiated by IRE1 , and the transcription factor ATF6, produced by proteolysis and release from the ER membrane, collaborate with ATF4 to induce the vast UPR transcriptional response. Transcriptional targets of the UPR include the ER protein folding machinery, the ER-associated degradation machinery, and many other components functioning in the secretory pathway (14). Although the UPR initially mitigates ER stress and as such confers cytoprotection, persistent and severe ER stress leads to activation of apoptosis that eliminates damaged cells (15,16).

Small-molecule therapeutics that inhibit the UPR and/or the Integrated Stress Response could be used in cancer as a single agent or in combination with other chemotherapeutics ( 1 7 , 1 8 , 1 9 ) , for enhancement of long-term memory (24 ,25) , in neurodegenerative and prion associated diseases (20) , in white matter disease (VWM) (23) and in biotechnology applications that would benefit from increased protein translation.

It is an object of the instant invention to provide novel compounds that prevent the translation of ATF4 or are inhibitors of the ATF4 pathway.

It is also an object of the present invention to provide pharmaceutical compositions that comprise a pharmaceutically acceptable excipient and compounds of Formula (I).

It is also an object of the present invention to provide a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering novel inhibitors of the ATF4 pathway.

SUMMARY OF THE INVENTION

The invention is directed to substituted heteroaryl derivatives. Specifically, the invention is directed to compounds according to Formula (I):

wherein defined below; or a salt thereof including a pharmaceutically acceptable salt thereof.

The present invention also relates to the discovery that the compounds of Formula (I) are active as inhibitors of the ATF4 pathway.

The present invention also relates to the discovery that the compounds of Formula (I) prevent the translation of ATF4.

This invention also relates to a method of treating Alzheimer’s disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating Parkinson’s disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating amyotrophic lateral sclerosis, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating Huntington’s disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating C re utzfeldt- Jakob Disease, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating progressive supranuclear palsy (PSP), which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating dementia, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating spinal cord injury, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating traumatic brain injury, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating ischemic stroke, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating diabetes, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating a disease state selected from:, myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias, which comprises administering to a subject in need thereof an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

This invention also relates to a method of treating an integrated stress response-associated disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the patient.

This invention also relates to a method of treating a disease associated with phosphorylation of elF2a in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.

This invention also relates to a method of treating a disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the patient, wherein the disease is selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome.

This invention also relates to a method of improving long-term memory in a patient, the method including administering a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the patient.

This invention also relates to a method of increasing protein expression of a cell or in vitro expression system, the method including administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof, to the cell or expression system.

This invention also relates to a method of treating an inflammatory disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.

This invention also relates to a method of using the compounds of Formula (I) in organ transplantation and in the transportation of organs for transplantation.

Also included in the present invention are methods of co-administering the presently invented compounds with further active ingredients.

Included in the present invention is a method for treating neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease,

C re utzfeldt- Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation that comprises administering the compounds of Formula (I).

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in therapy.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Alzheimer’s disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Parkinson’s disease syndromes.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of amyotrophic lateral sclerosis.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Huntington’s disease. The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of Creutzfeldt-Jakob Disease.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of progressive supranuclear palsy (PSP). The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of dementia.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of spinal cord injury.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of traumatic brain injury.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of ischemic stroke.

The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of diabetes. The invention also relates to a compound of Formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment of a disease state selected from:

myocardial infarction, cardiovascular disease, atherosclerosis, ocular diseases, and arrhythmias.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of an integrated stress response-associated disease.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease associated with phosphorylation of elF2a. The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease selected from the group consisting of: cancer, a

neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome. The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for improving long-term memory.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for increasing protein expression of a cell or in vitro expression system.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of inflammatory disease.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament in organ transplantation and in the transportation of organs for transplantation.

The invention also relates to the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease state selected from: neurodegenerative diseases, cancer, and other diseases/injuries associated with activated unfolded protein response pathways such as: Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, amyotrophic lateral sclerosis, progressive supranuclear palsy, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementias, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.

Included in the present invention are pharmaceutical compositions that comprise a pharmaceutical excipient and a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

The invention also relates to a pharmaceutical composition as defined above for use in therapy.

The invention also relates to a combination for use in therapy which comprises a therapeutically effective amount of (i) a compound of Formula (I) or a pharmaceutically acceptable salt thereof; and (ii) further active ingreadients. DETAILED DESCRIPTION OF THE INVENTION

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (I):

wherein:

A is heteroaryl optionally substituted by 1 to 3 substituents independently

selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -COOH, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

C and D are independently phenyl or pyridyl; is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted

Ci-6heteroalkylene, is further taken together with to form heterocycloalkyl; is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted

C1 -6heteroalkylene, is further taken together with to form heterocycloalkyl; R ¹ is selected from: hydrogen, Ci-6alkyl, substituted Ci -6alkyl, and heterocycloalkyl, or R^ is taken together with to from heterocycloalkyl; R® is selected from: hydrogen, Ci-6alkyl, substituted Ci -6alkyl, and heterocycloalkyl, or R® is taken together with l_2 to from heterocycloalkyl; R® and R® and are independently hydrogen, fluoro, chloro, bromo, iodo,

-OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2, -NO2, -C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH,

-SO3H, -SO2NH2,— NHC(0)NH2, -NHC(0)H, -NHOH, -OCF3, -OCHF2, substituted or unsubstituted Ci-6alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R2 and R^ are independently NR®, O, CH2, or S;

R® is selected from: hydrogen, Ci-6alkyl and Ci-6alkyl substituted 1 to 6 times by fluoro;

are independently 0 or 1 ; and

z® and z® are independently an integer from 0 to 5; or a salt thereof including a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (I).

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (II):

wherein:

A is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -COOH, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

1 1

C and D are independently phenyl or pyridyl;

| 2 js selected from: a bond, -CH2-, -NH-, CH2-0-, -0-CH2-,

-O-CH2-CH2-, and -CH2-CH2-O-, or | 2 js further taken together with R^ ³ to form imidazolidinyl or pyrrolidinyl;

| ³ js selected from: a bond, -CH2-, -NH-, CH2-O-, -O-CH2-,

-O-CH2-CH2-, and -CH2-CH2-O-, or ³ js further taken together with 1 to form imidazolidinyl or pyrrolidinyl;

R ^{1 1} is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and oxetanyl, or R11 is taken together with i ³ _l0 f _orm imidazolidinyl or pyrrolidinyl;

R ^{1 3} is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and oxetanyl, or

R^ ³ is taken together with | 2 to form imidazolidinyl or pyrrolidinyl;

R15 and R^® are independently hydrogen, methyl, or chloro;

R12 and R^ are O;

z12 and z14 are independently 0 or 1 ; and _Z 15 and are independently an integer from 0 to 5; or a salt thereof including a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (II).

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (III):

wherein:

2

A is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

2 2

C and D are independently phenyl or pyridyl l_22 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted Ci-6heteroalkylene; l_23 taken together with R21 to form heterocycloalkyl;

R23 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and heterocycloalkyl; R25 and R^S and are independently hydrogen, fluoro, chloro, bromo, iodo,

-OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2, -NO2, -C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH,

-SO3H, -SO2NH2,— NHC(0)NH2, -NHC(0)H, -NHOH, -OCF3, -OCHF2, substituted or unsubstituted Ci -6alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R22 and R24 are independently NR28, O, CH2, or S; R28 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;

z22 and z^4 are independently 0 or 1 ; and z25 and z^6 are independently an integer from 0 to 5; or a salt thereof including a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (III). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (IV):

wherein:

3

A is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

3 3

C and D are independently phenyl or pyridyl l_32 is selected from: a bond, -CH2-, -NH-, CH2-0-, -0-CH2-,

-0-CH2-CH2-, and -CH2-CH2-O-; is taken together with R31 to form imidazolidinyl or pyrrolidinyl; R33 is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and oxetanyl;

R35 and R^S are independently hydrogen, methyl, or chloro;

R32 and R^4 are O;

å32 and z^4 are independently 0 or 1 ; and

å35 and z^6 are independently an integer from 0 to 5; or a salt thereof including a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (IV).

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (V):

wherein:

A ⁴ is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

C ⁴ and D ⁴ are independently phenyl or pyridyl;

l_42 is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted Ci-6heteroalkylene;

L ⁴ ® is selected from: a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, cycloalkyl, substituted or unsubstituted Ci-6alkylene and substituted or unsubstituted Ci-6heteroalkylene;

R ⁴¹ is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and

heterocycloalkyl;

R ⁴ ® is selected from: hydrogen, Ci -6alkyl, substituted Ci-6alkyl, and

heterocycloalkyl;

R ⁴ ® and R ⁴ ® and are independently hydrogen, fluoro, chloro, bromo, iodo,

-OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2, -N02, -C(O)0H3, -CH(CH3)2, -CCH, -CH2CCH, -SO3H, -SO2NH2,— NHC(0)NH2, -NHC(0)H, -NHOH, -OCF3, -OCHF2, substituted or unsubstituted Ci -6alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

R42 and R44 are independently NR48, O, CH2, or S;

R48 is selected from: hydrogen, Ci -6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;

z42 and z44 are independently 0 or 1 ; and

z45 and z46 are independently an integer from 0 to 5; or a salt thereof including a pharmaceutically acceptable salt thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (V).

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VI):

wherein:

is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

are independently phenyl or pyridyl; l_52 and l_53 are independently a bond, -NH-, -0-, -S-, -S(O)-, -S(0)2-, substituted or unsubstituted Ci-6alkylene or substituted or unsubstituted

Ci-6heteroalkylene;

R55 and R56 and are independently hydrogen, fluoro, chloro, bromo, iodo,

-OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2, -N02, -C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH, -SO3H, -SO2NH2,— NHC(0)NH2, -NHC(0)H, -NHOH, -OCF3, -OCHF2, substituted or unsubstituted Ci-6alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R52 and R^4 are independently NR58, O, CH2, or S;

R58 is selected from: hydrogen, Ci-6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;

å52 and z^4 are independently 0 or 1 ; and

are independently an integer from 0 to 5; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VI). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (VII):

wherein

A® is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, oxo, and fluoro;

C® and D® are independently phenyl or pyridyl; l_®2 and L®® are independently: -CH2-O-, -O-CH2-, -O-CH2-CH2-, and

-CH2-CH2-O-;

R®® and R®® are independently hydrogen or chloro;

R®2 and R®4 are O;

Z®2 and z®4 are independently 0 or 1 ; and

Z®® and z®® are independently an integer from 0 to 5; and salts thereof. This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (VII). Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (XVI):

wherein:

is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl, -CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, and fluoro; are independently phenyl or pyridyl;

l_52 and l_53 are independently a bond, -NH-, -O-, -S-, -S(O)-, -S(0)2-, substituted or unsubstituted Ci-6alkylene or substituted or unsubstituted

Ci-6heteroalkylene;

R55 and R^S and are independently hydrogen, fluoro, chloro, bromo, iodo,

-OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2,

-COOH, -CONH2, -N02, -C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH, -SO3H, -SO2NH2,— NHC(0)NH2, -NHC(0)H, -NHOH, -OCF3, -OCHF2, substituted or unsubstituted Ci-6alkyl, substituted or

unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R52 and R^4 are independently NR^ o, CH2, or S;

R58 is selected from: hydrogen, Ci-6alkyl and Ci -6alkyl substituted 1 to 6 times by fluoro;

Z® ² and z® ⁴ are independently 0 or 1 ; and

Z®® and z®® are independently an integer from 0 to 5; and salts thereof.

This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XVI).

Included in the compounds of the invention and used in the methods of the invention are compounds of Formula (XVII):

wherein:

A® is heteroaryl optionally substituted by one or two substituents independently selected from: -OH, -CH3, -CF3, -CHF2, -CFH2, -CH(CH3)2, -cyclopropyl,

-CH20H, -CH2CH20H, -CH(OH)Me, -CH(NH2)Me, -OMe, -CN, and fluoro;

C® and D® are independently phenyl or pyridyl;

L® ² and L®® are independently: -CH2-O-, -O-CH2-, -O-CH2-CH2-, and

-CH2-CH2-O-;

R®® and R®® are independently hydrogen or chloro;

R® ² and R® ⁴ are O;

Z® ² and z® ⁴ are independently 0 or 1 ; and Z®® and z®® are independently an integer from 0 to 5; and salts thereof. This invention also relates to pharmaceutically acceptable salts of the compounds of Formula (XVII).

Included in the compounds of Formula (I) is:

A/,A/'-(pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide); and salts thereof including pharmaceutically acceptable salts thereof.

Included in the compounds of Formula (I) are:

A/,A/'-(pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(pyrimidine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(thiophene-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(thiophene-2,4-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(3-methylthiophene-2,5-diyl)bis(2-(4-chlorophenoxy)acet amide);

N,N'-(2,6-naphthyridine-1 ,4-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(6-hydroxypyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acet amide);

N,N'-(3-fluoropyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

N,N'-(6-(1 -hydroxyethyl)pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

N,N'-(6-(2-hydroxyethyl)pyridine-2,5-diyl)bis(2-(4-chloro phenoxy)acetamide);

N,N'-(4-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)ac etamide);

N,N'-(6-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

N,N'-(6-methylpyridine-2,5-diyl)bis(2-(4-chloro-3-fluorophen oxy)acetamide);

2-(4-chloro-3-fluorophenoxy)-N-(6-(2-(4-chlorophenoxy)ace tamido)-2- methylpyridin-3-yl)acetamide; N,N'-(3-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

2-(4-chloro-3-fluorophenoxy)-N-(5-(2-(4-chlorophenoxy)acetam ido)pyrazin-2- yl)acetamide;

2-(4-chlorophenoxy)-N-(6-(3-(4-chlorophenoxy)pyrrolidin-1 -yl)pyridin-3- yl)acetamide;

N,N'-(pyrimidine-2,5-diyl)bis(2-(4-chloro-3-fluorophenoxy)ac etamide);

N,N'-(4-methylpyrimidine-2,5-diyl)bis(2-(4-chlorophenoxy)ace tamide);

N-(2-((4-chlorobenzyl)amino)quinazolin-6-yl)-2-(4-chlorophen oxy)acetamide;

N,N'-(3-methylpyrazine-2,5-diyl)bis(2-(4-chlorophenoxy)ac etamide);

N,N'-(1 ,2,4,5-tetrazine-3,6-diyl)bis(2-(4-chlorophenoxy)acetamide);

and salts thereof including pharmaceutically acceptable salts thereof.

Also included in the compounds of Formula (I) are:



and salts thereof including pharmaceutically acceptable salts thereof.

Suitably, the compounds of the inventiom are:

A/,A/'-(pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(pyrimidine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(thiophene-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(thiophene-2,4-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(3-methylthiophene-2,5-diyl)bis(2-(4-chlorophenoxy)acet amide);

N,N'-(2,6-naphthyridine-1 ,4-diyl)bis(2-(4-chlorophenoxy)acetamide);

N,N'-(6-hydroxypyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acet amide);

N,N'-(3-fluoropyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

N,N'-(6-(1 -hydroxyethyl)pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide); N,N'-(6-(2-hydroxyethyl)pyridine-2,5-diyl)bis(2-(4-chlorophe noxy)acetamide);

N,N'-(4-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)ac etamide);

N,N'-(6-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

N,N'-(6-methylpyridine-2,5-diyl)bis(2-(4-chloro-3-fluorophen oxy)acetamide);

2-(4-chloro-3-fluorophenoxy)-N-(6-(2-(4-chlorophenoxy)acetam ido)-2- methylpyridin-3-yl)acetamide;

N,N'-(3-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide);

2-(4-chloro-3-fluorophenoxy)-N-(5-(2-(4-chlorophenoxy)acetam ido)pyrazin-2- yl)acetamide;

2-(4-chlorophenoxy)-N-(6-(3-(4-chlorophenoxy)pyrrolidin-1 -yl)pyridin-3- yl)acetamide;

N,N'-(pyrimidine-2,5-diyl)bis(2-(4-chloro-3-fluorophenoxy)ac etamide);

N,N'-(4-methylpyrimidine-2,5-diyl)bis(2-(4-chlorophenoxy)ace tamide);

N-(2-((4-chlorobenzyl)amino)quinazolin-6-yl)-2-(4-chlorophen oxy)acetamide; N,N'-(3-methylpyrazine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide); and

N,N'-(1 ,2,4,5-tetrazine-3,6-diyl)bis(2-(4-chlorophenoxy)acetamide); or a salt thereof including pharmaceutically acceptable salt thereof.

To clarify the obvious intent, in any of the above Formulas, when

moiety is 0, and the adjacent“R*” and“L*” moieties form a ring, such as a heterocycloalkyl, for example a pyrrolidinyl, the“R*” and“L*” moieties do not have to be adjacent in the ring.

Further, in any of the above Formulas, in a ^z moiety, it is understood that“R*” will be absent whenever“Z*” is 0. Further, in any of the above Formulas, in moiety, it is understood that whenever “z*” is 0, any substituent that could be an“R*” group, will be hydrogen.

Further, in all of the above Formulas the A ^* group is heteroaryl, which includes bicyclic groups wherein one of the two rings is not a heteroaryl. To clarify the obvious intent, for all A* groups in the above Formulas, when the A* group is bicyclic and one of the two rings is not a heteroaryl ring, the A* group is attached to the rest of the molecule through the heteroaryl ring.

In embodiments, R ⁵ is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2,

-NO2, -C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH, -SO3H, -SO2NH2,— NHC(0)NH2,

-NHC(0)H, -NHOH, -OCH3, -OCF3, -OCHF2, substituted or unsubstituted Ci- ₆ alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ⁵ is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -CH3, -OH, -CF3, -CN, -S(0)CH3, -NO2,

-C(0)CH3, -C(0)Ph, -CH(CH3)2, or— CCH. In embodiments, R ⁵ is— F. In embodiments,

R ⁵ is— Cl. In embodiments, R ⁵ is— Br. In embodiments, R ⁵ is— I. In embodiments, R ⁵ is substituted or unsubstituted Ci- ₆ alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ⁵ is unsubstituted Ci- ₆ alkylene, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R ⁵ is -OCH3. In embodiments, R ⁵ is -OCH2Ph. In embodiments, R ⁵ is - CH3. In embodiments, R ⁵ is -OH. In embodiments, R ⁵ is -CF3. In embodiments, R ⁵ is - CN. In embodiments, R ⁵ is -S(0)CH3. In embodiments, R ⁵ is -NO2. In embodiments, R ⁵ is -C(0)CH3. In embodiments, R ⁵ is -C(0)Ph. In embodiments, R ⁵ is -CH(CH3)2. In embodiments, R ⁵ is -CCH. In embodiments, R ⁵ is -CH2CCH. In embodiments, R ⁵ is - SO3H. In embodiments, R ⁵ is -SO2NH2. In embodiments, R ⁵ is— NHC(0)NH2. In embodiments, R ⁵ is -NHC(0)H. In embodiments, R ⁵ is -NHOH. In embodiments, R ⁵ is- OCH3. In embodiments, R is -OCF3. In embodiments, R ⁵ is -OCHF2.

In embodiments, R ⁶ is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3,

-OCH2Ph, -C(0)Ph, -CH3, -CF3, -CN, -S(0)CH3, -OH, -NH2, -COOH, -CONH2, -NO2,

-C(0)CH3, -CH(CH3)2, -CCH, -CH2CCH, -SO3H, -SO2NH2,— NHC(0)NH2, -NHC(0)H, -

NHOH, -OCH3, -OCF3, -OCHF2, substituted or unsubstituted Ci- ₆ alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ⁶ is independently hydrogen, fluoro, chloro, bromo, iodo, -OCH3, -OCH2Ph, -CH3, -OH, -CF3, -CN, -S(0)CH3, -NO2, -C(0)CH3,

-C(0)Ph, -CH(CH3)2, or— CCH. In embodiments, R ⁶ is— F. In embodiments, R ⁶ is— Cl. In embodiments, R ⁶ is— Br. In embodiments, R ⁶ is— I. In embodiments, R ⁶ is substituted or unsubstituted Ci- ₆ alkylene, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In embodiments, R ⁶ is unsubstituted Ci- ₆ alkylene, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, unsubstituted aryl, or unsubstituted heteroaryl. In embodiments, R ⁶ is -OCH3. In embodiments, R ⁶ is -OCH2Ph. In embodiments, R ⁶ is - CH3. In embodiments, R ⁶ is -OH. In embodiments, R ⁶ is -CF3. In embodiments, R ⁶ is - CN. In embodiments, R ⁶ is -S(0)CH3. In embodiments, R ⁶ is -NO2. In embodiments, R ⁶ is -C(0)CH3. In embodiments, R ⁶ is -C(0)Ph. In embodiments, R ⁶ is -CH(CH3)2. In embodiments, R ⁶ is -CCH. In embodiments, R ⁶ is -CH2CCH. In embodiments, R ⁶ is - SO3H. In embodiments, R ⁶ is -SO2NH2. In embodiments, R ⁶ is— NHC(0)NH2. In embodiments, R ⁶ is -NHC(0)H. In embodiments, R ⁶ is -NHOH. In embodiments, R ⁶ is - OCH3. In embodiments, R ⁶ is -OCF3. In embodiments, R ⁶ is -OCHF2.

In embodiments, R ² is NR ⁸ . In embodiments, R ² is NH. In embodiments, R ² is O. In embodiments, R ² is S. In embodiments, R ⁴ is NR ⁸ . In embodiments, R ⁴ is NH. In embodiments, R ⁴ is O. In embodiments, R ⁴ is S. In embodiments, R ² and R ⁴ are NH. In embodiments, R ² and R ⁴ are O. In embodiments, R ² and R ⁴ are S. In embodiments, R ² and R ⁴ are NR ⁸ .

In embodiments, L ² is a bond. In embodiments, L ² is a substituted or unsubstituted Ci_ ₆ alkylene. In embodiments, L ² is a substituted or unsubstituted Ci- ₆ heteroalkylene. In embodiments, L is L -L -L and L is bonded to the substituted or unsubstituted phenyl, which may be substituted with R . is a bond,— O-, -S-, -NH-, -S(O)-, or—

S(0)2-. L is a bond or substituted or unsubstituted Ci- ₆ alkylene. is a bond, -O-, or — NH-. In embodiments, L is a bond. In embodiments, L is— O-. In embodiments,

L ^2A is -S-. In embodiments, l_ ^2A is -NH-. In embodiments, l_ ^2A is -S(O)-. In

embodiments, L is— S(0)2-. In embodiments, L is a bond. In embodiments, L is a substituted or unsubstituted Ci- ₆ alkylene. In embodiments, L is an unsubstituted Ci_

₆ alkylene. In embodiments, L is a substituted or unsubstituted C1-C5 alkylene. In embodiments, L is an unsubstituted C1 -C5 alkylene. In embodiments, L is a substituted or unsubstituted Ci-C ₄ alkylene. In embodiments, L is an unsubstituted C1-

C ₄ alkylene. In embodiments, L is a substituted or unsubstituted C1-C3 alkylene. In embodiments, L is an unsubstituted C1 -C3 alkylene. In embodiments, L is a substituted C1-C5 alkylene. In embodiments, L is a substituted C1-C6 alkylene. In embodiments, L is a substituted C1-C5 alkylene. In embodiments, L is a substituted

Ci-C ₄ alkylene. In embodiments, L is a C1-C6 alkylene substituted with— CF3. In o op op embodiments, L is a bond. In embodiments, L is -O-. In embodiments, L is— NH-. In embodiments, L is a bond; L is unsubstituted methylene; and L is -0-.

In embodiments, L ³ is a bond. In embodiments, L ³ is a substituted or unsubstituted Ci_ ₆ alkylene. In embodiments, L ³ is a substituted or unsubstituted Ci- ₆ heteroalkylene. In embodiments, L ³ is |_ ^3A -|_ ^3B -I_ ^3C and l_ ^3A is bonded to the substituted or unsubstituted phenyl, which may be substituted with R ⁵ . I_ ^3A is a bond,— O-, -S-, -NH-, -S(O)-, or— S(0)2-. L is a bond or substituted or unsubstituted Ci- ₆ alkylene. is a bond, -O-, or

— NH-. In embodiments, L is a bond. In embodiments, L is— O-. In embodiments,

L ^3A is -S-. In embodiments, l_ ^3A is -NH-. In embodiments, l_ ^3A is -S(O)-. In

embodiments, L is— S(0)2-. In embodiments, L is a bond. In embodiments, L is a substituted or unsubstituted Ci- ₆ alkylene. In embodiments, L is an unsubstituted Ci_

₆ alkylene. In embodiments, L is a substituted or unsubstituted C1-C5 alkylene. In embodiments, L is an unsubstituted C1 -C5 alkylene. In embodiments, L is a substituted or unsubstituted Ci-C ₄ alkylene. In embodiments, L is an unsubstituted C1- C ₄ alkylene. In embodiments, L is a substituted or unsubstituted Ci-C3alkylene. In embodiments, L is an unsubstituted C1 -C3 alkylene. In embodiments, L is a substituted C1-C5 alkylene. In embodiments, L is a substituted C1-C6 alkylene. In embodiments, L is a substituted C1-C5 alkylene. In embodiments, L is a substituted

Ci-C ₄ alkylene. In embodiments, L is a C1-C6 alkylene substituted with— CF3. In embodiments, L is a bond. In embodiments, L is -O-. In embodiments, L is— NH-. In embodiments, L is a bond; L is unsubstituted methylene; and L is -O-.

In embodiments, L ³ is taken together with R ¹ to form heterocycloalkyl. Suitably the heterocycloalkyl is imidazolidinyl or pyrrolidinyl. Suitably the heterocycloalkyl is imidazolidinyl. Suitably the heterocycloalkyl is pyrrolidinyl.

In embodiments, L ² is taken together with R ³ to form heterocycloalkyl. Suitably the heterocycloalkyl is imidazolidinyl or pyrrolidinyl. Suitably the heterocycloalkyl is imidazolidinyl. Suitably the heterocycloalkyl is pyrrolidinyl. In embodiments, L ²² is taken together with R ²³ to form heterocycloalkyl. Suitably the heterocycloalkyl is imidazolidinyl or pyrrolidinyl. Suitably the heterocycloalkyl is imidazolidinyl. Suitably the heterocycloalkyl is pyrrolidinyl.

In embodiments, L ²³ is taken together with R ²¹ to form heterocycloalkyl. Suitably the heterocycloalkyl is imidazolidinyl or pyrrolidinyl. Suitably the heterocycloalkyl is imidazolidinyl. Suitably the heterocycloalkyl is pyrrolidinyl.

In embodiments, L is taken together with R to form heterocycloalkyl. Suitably the heterocycloalkyl is imidazolidinyl or pyrrolidinyl. Suitably the heterocycloalkyl is imidazolidinyl. Suitably the heterocycloalkyl is pyrrolidinyl.

In embodiments, L ⁴² is taken together with R ⁴¹ to form imidazolidinyl or pyrrolidinyl. Suitably L ⁴² is taken together with R ⁴¹ to form imidazolidinyl. Suitably L ⁴² is taken together with R ⁴¹ to form pyrrolidinyl.

In embodiments, L ⁴³ is taken together with R ⁴³ to form imidazolidinyl or pyrrolidinyl. Suitably L ⁴³ is taken together with R ⁴³ to form imidazolidinyl. Suitably L ⁴³ is taken together with R ⁴³ to form pyrrolidinyl.

In embodiments, L is taken together with R to form imidazolidinyl or pyrrolidinyl.

Suitably L is taken together with R to form imidazolidinyl. Suitably L is taken together with R to form pyrrolidinyl.

ln embodiments, L ⁶² is taken together with R ⁶¹ to form imidazolidinyl or pyrrolidinyl. Suitably L ⁶² is taken together with R ⁶¹ to form imidazolidinyl. Suitably L ⁶² is taken together with R ⁶¹ to form pyrrolidinyl.

In embodiments, L ⁶³ is taken together with R ⁶³ to form imidazolidinyl or pyrrolidinyl. Suitably L ⁶³ is taken together with R ⁶³ to form imidazolidinyl. Suitably L ⁶³ is taken together with R ⁶³ to form pyrrolidinyl.

In embodiments, the symbol z^ is 0. In embodiments, the symbol z^ is 1 . In embodiments, the symbol z ⁴ is 0. In embodiments, the symbol z ⁴ is 1 . In embodiments, the symbols z^ and z ⁴ are 0. In embodiments, the symbols z^ and z ⁴ are 1 . In embodiments, the symbol z® is 0. In embodiments, the symbol z® is 1 . In embodiments, the symbol z® is 2. In embodiments, the symbol z® is 3. In embodiments, the symbol z® is 4. In embodiments, the symbol z® is 0. In embodiments, the symbol z® is 1 . In embodiments, the symbol z® is 2. In embodiments, the symbol z® is 3. In embodiments, the symbol z® is 4.

In embodiments, any of A, A ¹ , A ² , A ³ , A ⁴ , A ⁵ , or A ⁶ , is selected from: pyridinyl, thiophenyl, thiadiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, naphthyridinyl, isoquinoline, 2,3-dihydro-1 /-/-pyrrolo[3,4-c]pyridinyl, and 6,7-dihydro-5/-/-cyclopental[c]pyridinyl.

The skilled artisan will appreciate that salts, including pharmaceutically acceptable salts, of the compounds according to Formula (I) may be prepared. Indeed, in certain embodiments of the invention, salts including pharmaceutically-acceptable salts of the compounds according to Formula (I) may be preferred over the respective free or unsalted compound. Accordingly, the invention is further directed to salts, including pharmaceutically-acceptable salts, of the compounds according to Formula (I).

The salts, including pharmaceutically acceptable salts, of the compounds of the invention are readily prepared by those of skill in the art.

Typically, the salts of the present invention are pharmaceutically acceptable salts. Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.

Representative pharmaceutically acceptable acid addition salts include, but are not limited to, 4-acetamidobenzoate, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate (besylate), benzoate, bisulfate, bitartrate, butyrate, calcium edetate, camphorate, camphorsulfonate (camsylate), caprate (decanoate), caproate (hexanoate), caprylate (octanoate), cinnamate, citrate, cyclamate, digluconate, 2,5-dihydroxybenzoate, disuccinate, dodecylsulfate (estolate), edetate (ethylenediaminetetraacetate), estolate (lauryl sulfate), ethane-1 ,2-disulfonate (edisylate), ethanesulfonate (esylate), formate, fumarate, galactarate (mucate), gentisate (2,5-dihydroxybenzoate), glucoheptonate (gluceptate), gluconate, glucuronate, glutamate, glutarate, glycerophosphorate, glycolate, hexylresorcinate, hippurate, hydrabamine (A/,A/'-di(dehydroabietyl)-ethylenediamine), hydrobromide, hydrochloride, hydroiodide, hydroxynaphthoate, isobutyrate, lactate, lactobionate, laurate, malate, maleate, malonate, mandelate, methanesulfonate (mesylate), methylsulfate, mucate, naphthalene-1 ,5-disulfonate (napadisylate), naphthalene-2-sulfonate (napsylate), nicotinate, nitrate, oleate, palmitate, p- aminobenzenesulfonate, p-aminosalicyclate, pamoate (embonate), pantothenate, pectinate, persulfate, phenylacetate, phenylethylbarbiturate, phosphate, polygalacturonate, propionate, p-toluenesulfonate (tosylate), pyroglutamate, pyruvate, salicylate, sebacate, stearate, subacetate, succinate, sulfamate, sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate), thiocyanate, triethiodide, undecanoate, undecylenate, and valerate.

Representative pharmaceutically acceptable base addition salts include, but are not limited to, aluminium, 2-amino-2-(hydroxymethyl)-1 ,3-propanediol (TRIS,

tromethamine), arginine, benethamine (/V-benzylphenethylamine), benzathine (A/, A/ - dibenzylethylenediamine), b/s-(2-hydroxyethyl)amine, bismuth, calcium, chloroprocaine, choline, clemizole (1 -p chlorobenzyl-2-pyrrolildine-1’-ylmethylbenzimidazole),

cyclohexylamine, dibenzylethylenediamine, diethylamine, diethyltriamine, dimethylamine, dimethylethanolamine, dopamine, ethanolamine, ethylenediamine, L-histidine, iron, isoquinoline, lepidine, lithium, lysine, magnesium, meglumine (/V-methylglucamine), piperazine, piperidine, potassium, procaine, quinine, quinoline, sodium, strontium, t- butylamine, and zinc.

The compounds according to Formula (I) may contain one or more asymmetric centers (also referred to as a chiral center) and may, therefore, exist as individual enantiomers, diastereomers, or other stereoisomeric forms, or as mixtures thereof. Chiral centers, such as chiral carbon atoms, may be present in a substituent such as an alkyl group. Where the stereochemistry of a chiral center present in a compound of Formula (I), or in any chemical structure illustrated herein, if not specified the structure is intended to encompass all individual stereoisomers and all mixtures thereof. Thus, compounds according to Formula (I) containing one or more chiral centers may be used as racemic mixtures, enantiomerically or diastereomerically enriched mixtures, or as enantiomerically or diastereomerically pure individual stereoisomers.

The compounds according to Formula (I) and pharmaceutically acceptable salts thereof may contain isotopically-labelled compounds, which are identical to those recited in Formula (I) and following, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of such isotopes include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, sulphur, fluorine, iodine, and chlorine, such as 2H, 3H, 1 1 C, 13C, 14C, 15N, 170, 180, 31 P, 32P, 35S, 18F, 36CI, 1231 and 1251.

Isotopically-labelled compounds, for example those into which radioactive isotopes such as 3H or 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e. , 3H, and carbon-14, i.e. , 14C, isotopes are particularly preferred for their ease of preparation and detectability. 1 1 C and 18F isotopes are particularly useful in PET (positron emission tomography), and 1251 isotopes are particularly useful in SPECT (single photon emission computerized tomography), both are useful in brain imaging. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds can generally be prepared by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.

The compounds according to Formula (I) may also contain double bonds or other centers of geometric asymmetry. Where the stereochemistry of a center of geometric asymmetry present in Formula (I), or in any chemical structure illustrated herein, is not specified, the structure is intended to encompass the trans (E) geometric isomer, the cis (Z) geometric isomer, and all mixtures thereof. Likewise, all tautomeric forms are also included in Formula (I) whether such tautomers exist in equilibrium or predominately in one form.

The compounds of Formula (I) or salts, including pharmaceutically acceptable salts, thereof may exist in solid or liquid form. In the solid state, the compounds of the invention may exist in crystalline or noncrystalline form, or as a mixture thereof. For compounds of the invention that are in crystalline form, the skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed wherein solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates wherein water is the solvent that is incorporated into the crystalline lattice are typically referred to as "hydrates." Hydrates include stoichiometric hydrates as well as compositions containing vaiable amounts of water.

The skilled artisan will further appreciate that certain compounds of Formula (I) or salts, including pharmaceutically acceptable salts thereof that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as "polymorphs." Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, for example, by changing or adjusting the reaction conditions or reagents, used in making the compound. For example, changes in temperature, pressure, or solvent may result in polymorphs. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

While aspects for each variable have generally been listed above separately for each variable this invention includes those compounds in which several or each aspect in Formula (I) is selected from each of the aspects listed above. Therefore, this invention is intended to include all combinations of aspects for each variable.

Definitions

“Alkyl” and“alkylene”, and derivatives thereof, refer to a hydrocarbon chain having the specified number of“member atoms”. Alkyl being monovalent and alkylene being bivalent. For example, C-i -Cg alkyl refers to an alkyl group having from 1 to 6 member carbon atoms. Alkyl and alkylene groups may be saturated, unsaturated, straight or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl and alkylene include: methyl, ethyl, ethylene, propyl (n-propyl and isopropyl), butene, butyl (n-butyl, isobutyl, and t-butyl), pentyl and hexyl.

“Alkoxy” refers to an -O-alkyl group wherein“alkyl” is as defined herein. For example, C-| -C4alkoxy refers to an alkoxy group having from 1 to 4 member carbon atoms.

Representative branched alkoxy groups have one, two, or three branches. Examples of such groups include methoxy, ethoxy, propoxy, and butoxy.

“Aryl” refers to an aromatic hydrocarbon ring. Aryl groups are monocyclic, bicyclic, and tricyclic ring systems having a total of five to fourteen ring member carbon atoms, wherein at least one ring system is aromatic and wherein each ring in the system contains 3 to 7 member carbon atoms, such as phenyl, naphthalene, tetrahydronaphthalene and biphenyl. Suitably aryl is phenyl.

“Cycloalkyl”, unless otherwise defined, refers to a saturated or unsaturated non aromatic hydrocarbon ring having from three to seven carbon atoms. Cycloalkyl groups are monocyclic ring systems. For example, C3-C7 cycloalkyl refers to a cycloalkyl group having from 3 to 7 member carbon atoms. Examples of cycloalkyl as used herein include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptyl. Suitably cycolalkyl is cyclopropyl.

“Halo” refers to fluoro, chloro, bromo, and iodo.

"Heteroaryl” refers to a monocyclic aromatic 5 or 6 member ring, containing 1 to 5 carbon atoms and containing 1 to 3 heteroatoms, provided that when the number of carbon atoms is 3, the aromatic ring contains at least two heteroatoms, or to such heteroaromatic ring fused to another ring, such as a heteroaryl ring, an aryl ring, a heterocyclic ring, or a cycloalkyl ring. Heteroaryl groups containing more than one heteroatom may contain different heteroatoms.

Suitable examples of monocyclic heteroaryls for use herein includes but is not limited to: furanyl, pyrazolyl, imidazo!y!, indolizinyl, naphthyridinyl, oxazolyl, oxadiazolyl, pyridyl, pyrrolyl, pyrimidyl, isothiazolyl, furazanyl, pyrimidinyl, tetrazinyl, isoxazolyl, thienyl, thiophenyl, triazolyl, triazinyl, tetrazolyl, thiazolyl, pyridinyl, thiophenyl, thiadiazolyl, pyrazinyl, pyrimidinyl, and pyridazinyl. Suitably, pyridinyl, thiophenyl, thiadiazolyl, pyrazinyl, pyrimidinyl, or pyridazinyl. Suitably, tetrazinyl.

Suitable examples of bicyclic heteroaryls for use herein includes but is not limited to: 1 H- pyrazolo[3,4-d]pyrimidinyl, 1 H-pyrrolo[2,3-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, thieno[3,2-c]pyridinyl, thieno[2,3-d]pyrimidinyl, furo[2,3-c]pyridinyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, pteridinyl, cinnolinyl, oxothiadiazolyl, phthalazinyl, pyrazolopyrimidinyl, pyrazolopyridinyl, pyrrolizinyl, quinoxalinyl, quinazolinyl, quinolinyl, quinolizinyl, tetrazolopyrimidinyl, triazolopyrimidinyl, azabenzimidazolyl, tetrahydrobenzimidazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzothienyl, imidazo[4.5-c]pyridinyl, imidazo[4.5- b] pyridinyl, furopyrimidinyl, napthyridinyl, benzothiophenyl, benzopyrazinyl, benzotriazolyl, benzotriazinyl, benzo[1 ,4]dioxanyl, 9/-/-a-carbolinyl, 2,3-dihydro-1 /-/-pyrrolo[3,4-c]pyridinyl; and 6,7-dihyd ro-5/-/-cyclopental[c]pyridinyl. Suitably, naphthyridinyl; isoquinolinyl; 2,3- dihydro-1 /-/-pyrrolo[3,4-c]pyridinyl; or 6,7-dihyd ro-5/-/-cyclopental[c]pyridinyl. Suitably, quinazolinyl.

“Heterocycloalkyl” refers to a saturated or unsaturated non-aromatic ring containing 4 to 12 member atoms, of which 1 to 1 1 are carbon atoms and from 1 to 6 are heteroatoms. Heterocycloalkyl groups containing more than one heteroatom may contain different heteroatoms. Heterocycloalkyl groups are monocyclic ring systems or a monocyclic ring fused with an aryl ring having from 3 to 6 member atoms. Heterocycloalkyl includes: pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, pyranyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothienyl, pyrazolidinyl, benzopyranyl, oxazolidinyl, imidazolidinyl, oxetanyl, thiazolidinyl, piperidinyl, homopiperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 1 ,3- dioxolanyl, 1 ,3-dioxanyl, 1 ,4-dioxanyl, 1 ,3-oxathiolanyl, 1 ,3-oxathianyl, 1 ,3-dithianyl, 1 ,3- oxazolidinly, hexahydro-1 H-azepin, piperidinyl, 1 ,2,3,6-tetrahydro-pyridinyl and azetidinyl. Suitably, “heterocycloalkyl” includes: piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, imidazolidinyl, oxetanyl, and pyrrolidinyl. Suitably,“heterocycloalkyl” is: imidazolidinyl or pyrrolidinyl.

“Heteroatom” refers to a nitrogen, sulphur or oxygen atom.

"Heteroalkyl" and“heteroalkylene” by itself or in combination with another term, means, unless otherwise stated, a non-cyclic stable straight or branched chain, or combinations thereof, including at least one carbon atom and at least one heteroatom selected from the group consisting of O, N, P, Si, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized. Heteroalkyl being monovalent and heteroalkylene being bivalent. The heteroalkyl and heteroalkylene groups may be taken together with another substituent to form a heterocycloalkyl group. The heteroatom(s) O, N, P, S, and Si may be placed at any interior position of the heteroalkyl or heteroalkylene group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to:

-CH2-CH2-O-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)2, -CH2-S-CH2-CH3, -CH2-CH3, -S(0)-CH3, -CH2-CH2-S(0)2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2-CH=N-OCH3,

-CH=CHN(CH3)2, -O-CH3, -O-CH2-CH3, -CN. Examples include, but are not limited to: -CH3, -CH2-, -CH2-CH2-O-CH2-, CH2-CH2-NH-CH2-, -CH2-CH2-N(CH3)CH2-,

-CH2-S-CH2-CH2-, -CH2-CH2-, -S(0)-CH2-, -CH2-CH2-S(0)2-CH2-, -CH=CH-0-CH2-,

-Si(CH3)2CH2-, -N(CH3)CH2 -O-CH2-CH2-CH2-, -CH2-CH=N-OCH2-,

-CH=CHN(CH3)CH2-, -O-CH2-, and -O-CH2-CH2-. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and— CH2-0-Si(CH3)3.

“Substituted” as used herein, unless otherwise defined, is meant that the subject chemical moiety has from one to nine substituents, suitably from one to five substituents, selected from the group consisting of: fluoro,

chloro,

bromo,

iodo,

Cl-6alkyl,

Ci-6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-OCi -6alkyl,

-OCi -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

mercapto,

-SR ^X , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

-S(0)R ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-S(0)2H,

-S(0)2R ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

oxo,

hydroxy,

amino,

-NHR ^X , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-NR ^x1 R ^x2 , where R ^x1 and R ^{5 2} are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6

substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

guanidino,

-C(0)0H,

-C(0)0R ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-C(0)NH2, -C(0)NHR ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN, -C(0)NR ^x1 R ^x2 , where R ^x1 and R ^{5 2} are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6

substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

-S(0)2NH2,

-S(0)2NHR ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-S(0)2NR ^x1 R* ² , where R ^x1 and R ^{5 2} are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6

substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

-NHS(0)2H, -NHS(0)2R ^X , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-NHC(0)H,

-NHC(0)R ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents

independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

-NHC(0)NH2,

-NHC(0)NHR ^x , where R ^x is selected from Ci-6alkyl, and Ci -6alkyl substituted with from 1 to 6 substituents independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, and -CN,

-NHC(0)NR ^x1 R^, where R ^x1 and R ^{5 2} are each independently selected from Ci-6alkyl, and Ci-6alkyl substituted with from 1 to 6

Substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

nitro, and

cyano.

Suitably“substituted” means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro,

chloro,

bromo,

iodo,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

-OCl -4alkyl,

-OCi -4alkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, oxo, -OH, -COOH, -NH2, and -CN,

-SH, -S(0)2H,

0X0,

hydroxy,

amino,

-NHR ^X , where R ^x is selected from Ci-4alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,

-NR ^x1 R ^x2 , where R ^x1 and R ^{5 2} are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,

guanidino,

-C(0)0H,

-C(0)0R ^x , where R ^x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,

-C(0)NH2,

-C(0)NHR ^x , where R ^x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,

-C(0)NR ^x1 R* ² , where R ^x1 and R ^{5 2} are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro, -S(0)2NH2,

-NHS(0)2H,

-NHC(0)H,

-NHC(0)NH2,

nitro, and

cyano.

Suitably“substituted” means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro,

chloro,

bromo,

iodo,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 4 substituents

independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -NHCl-3alkyl, -N(Cl -3alkyl)2, -OCl-4alkyl and -CN,

-OCl -4alkyl,

-OCi -4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH,

-COOH, -NH2, -NHCl-3alkyl, -N(Cl -3alkyl)2, and -CN,

-SH,

-S(0)2H, 0X0,

hydroxy,

amino,

-NHR ^X , where R ^x is selected from Ci-4alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,

-NR ^x1 R ^x2 ,

c1 vO

where R and R are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,

guanidino,

-C(0)0H,

-C(0)0R ^x , where R ^x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,

-C(0)NH2,

-C(0)NHR ^x , where R ^x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,

-C(0)NR ^x1 R ³ ' ² , where R ^x1 and R ^{5 2} are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,

-S(0)2NH2, -NHS(0)2H,

-NHC(0)H,

-NHC(0)NH2,

nitro, and

cyano.

Suitably“substituted” means the subject chemical moiety has from one to four substituents selected from the group consisting of: fluoro,

chloro,

bromo,

iodo,

Cl-4alkyl,

Ci-4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, -OCH3, -OCH2CH3, and -CN,

-OCl -4alkyl,

-OCi -4alkyl substituted with from 1 to 4 substituents independently selected from: fluoro, oxo, -OH, -COOH, -NH2, -NHCH3, -N(CH3)2, and -CN,

-SH,

-S(0)2H,

oxo, hydroxy,

amino,

-NHR ^X , where R ^x is selected from Ci-4alkyl, and Ci -6alkyl substituted one to 4 times by fluoro,

-NR ^x1 R ^x2 , where R ^x1 and R ^{5 2} are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,

guanidino,

-C(0)0H,

-C(0)0R ^x , where R ^x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,

-C(0)NH2,

-C(0)NHR ^x , where R ^x is selected from Ci-4alkyl, and Ci -4alkyl substituted one to four times by fluoro,

-C(0)NR ^x1 R* ² , where R ^x1 and R ^{5 2} are each independently selected from Ci-4alkyl, and Ci-4alkyl substituted one to four times by fluoro,

-S(0)2NH2,

-NHS(0)2H, -NHC(0)H,

-NHC(0)NH2,

nitro, and

cyano.

As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. Standard single-letter or three-letter abbreviations are generally used to designate amino acid residues, which are assumed to be in the L-configuration unless otherwise noted. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

Ac (acetyl);

AC ₂ 0 (acetic a n hyd rid e) ;

ACN (acetonitrile);

AIBN (azobis(isobutyronitrile));

BINAP (2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl);

BMS (borane - dimethyl sulphide complex);

Bn (benzyl);

Boc (tert-Butoxycarbonyl);

BOC ₂ 0 (di-fe/f-butyl dicarbonate);

BOP (Benzotriazole-l-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate); CAN (cerric ammonium nitrate);

Cbz (benzyloxycarbonyl);

CSI (chlorosulfonyl isocyanate);

CSF (cesium fluoride);

DABCO (1 ,4-Diazabicyclo[2.2.2]octane);

DAST (Diethylamino)sulfur trifluoride); DBU (1 ,8-Diazabicyclo[5.4.0]undec-7-ene);

DCC (Dicyclohexyl Carbodiimide);

DCE (1 ,2-dichloroethane);

DCM (dichloromethane);

DDQ (2,3-Dichloro-5,6-dicyano-1 ,4-benzoquinone);

ATP (adenosine triphosphate);

Bis-pinacolatodiboron (4,4,4',4',5,5,5',5'-Octamethyl-2,2'-bi-1 ,3,2-dioxaborolane);

BSA (bovine serum albumin);

C18 (refers to 18-carbon alkyl groups on silicon in HPLC stationary phase);

CH ₃ CN (acetonitrile);

Cy (cyclohexyl);

DCM (dichloromethane);

DIPEA (Hiinig’s base, A/-ethyl-A/-(1-methylethyl)-2-propanamine);

Dioxane (1 ,4-dioxane);

DMAP (4-dimethylaminopyridine);

DME (1 ,2-dimethoxyethane);

DMEDA (A/,A/-dimethylethylenediamine);

DMF (A/,A/-dimethylformamide);

DMSO (dimethylsulfoxide);

DPPA (diphenyl phosphoryl azide);

EDC (A/-(3-dimethylaminopropyl)-A/’ethylcarbodiimide);

EDTA (ethylenediaminetetraacetic acid);

EtOAc (ethyl acetate);

EtOH (ethanol);

Et ₂ 0 (diethyl ether);

HEPES (4-(2-hydroxyethyl)-1 -piperazine ethane sulfonic acid);

HATU (0-(7-Azabenzotriazol-1-yl)-A/,A/,A/',A/-tetramethyluronium hexafluorophosphate); HOAt (1-hydroxy-7-azabenzotriazole); HOBt (1-hydroxybenzotriazole);

HOAc (acetic acid);

HPLC (high pressure liquid chromatography);

HMDS (hexamethyldisilazide);

Hunig’s Base (A/,A/-Diisopropylethylamine);

IPA (isopropyl alcohol);

Indoline (2,3-dihydro-1 /-/-indole);

KHMDS (potassium hexamethyldisilazide);

LAH (lithium aluminum hydride);

LDA (lithium diisopropylamide);

LHMDS (lithium hexamethyldisilazide);

MeOH (methanol);

Me (-CH3);

MTBE (methyl tert-butyl ether);

mCPBA (m-chloroperbezoic acid);

NaHMDS (sodium hexamethyldisilazide);

NBS (/V-bromosuccinimide);

PE (petroleum ether);

Pd ₂ (dba) ₃ (Tris(dibenzylideneacetone)dipalladium(O);

Pd(dppf)CI ₂ .DCM Complex ([1 ,1

Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).dichlo romethane complex); PyBOP (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate); PyBrOP (bromotripyrrolidinophosphonium hexafluorophosphate);

RPHPLC (reverse phase high pressure liquid chromatography);

RT (room temperature);

Sat. (saturated);

SFC (supercritical fluid chromatography);

SGC (silica gel chromatography); SM (starting material);

TLC (thin layer chromatography);

TEA (triethylamine);

TEMPO (2,2,6,6-Tetramethylpiperidine 1 -oxyl, free radical);

TFA (trifluoroacetic acid); and

THF (tetrahydrofuran).

All references to ether are to diethyl ether and brine refers to a saturated aqueous solution of NaCI. COMPOUND PREPARATION

The compounds according to Formula (I) are prepared using conventional organic synthetic methods. Suitable synthetic routes are depicted below in the following general reaction schemes. All of the starting materials are commercially available or are readily prepared from commercially available starting materials by those of skill in the art.

The skilled artisan will appreciate that if a substituent described herein is not compatible with the synthetic methods described herein, the substituent may be protected with a suitable protecting group that is stable to the reaction conditions. The protecting group may be removed at a suitable point in the reaction sequence to provide a desired intermediate or target compound. Suitable protecting groups and the methods for protecting and de-protecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rd ed.), John Wiiey & Sons, NY (1999). In some instances, a substituent may be specifically selected to be reactive under the reaction conditions used. Under these circumstances, the reaction conditions convert the selected substituent into another substituent that is either useful as an intermediate compound or is a desired substituent in a target compound. As used in the Schemes,“Ar” groups represent corresponding groups on any of Formulas I to VII. “G” groups are C, S, O or N provided at least one“G” group is other then C. The compounds of Formulas I to VII can be prepared generally as described in the Schemes using appropriate substitutions for starting materials.

Scheme 1

Scheme 2

Methods of Use The compounds according to Formula (I) and pharmaceutically acceptable salts thereof are inhibitors of the ATF4 pathway. Compounds which are inhibitors of the ATF4 pathway are readily identified by exhibiting activity in the ATF4 Cell Based Assay below. These compounds are potentially useful in the treatment of conditions wherein the underlying pathology is attributable to (but not limited to) modulation of the elF2alpha pathway, for example, neurodegenerative disorders, cancer, cardiovascular and metabolic diseases. Accordingly, in another aspect the invention is directed to methods of treating such conditions. The Integrated Stress Response (ISR) is a collection of cellular stress response pathways that converge in phosphorylation of the translation initiation factor elF2a resulting in a reduction in overall translation in cells. Mammalian cells have four elF2a kinases that phosphorylate this initiation factor in the same residue (serine 51); PERK is activated by the accumulation of unfolded proteins in the endoplasmic reticulum (ER), GCN2 is activated by amino acid starvation, PKR by viral infection and HRI by heme deficiency. Activation of these kinases decreases bulk protein synthesis but it also culminates in increased expression of specific mRNAs that contain uORFs. Two examples of these mRNAs are the transcription factor ATF4 and the pro-apoptotic gene CHOP. Phosphorylation of elF2a upon stress and the concomitant reduction in protein translation has been shown to both have cyto protective and cytotoxic effects depending on the cellular context and duration and severity of the stress. An integrated stress response-associated disease is a disease characterized by increased activity in the integrated stress response (e.g. increased phosphorylation of elF2a by an elF2a kinase compared to a control such as a subject without the disease). A disease associated with phosphorylation of elF2a is disease characterized by an increase in phosphorylation of elF2a relative to a control, such as a subject without the disease.

Activation of PERK occurs upon ER stress and hypoxic conditions and its activation and effect on translation has been shown to be cytoprotective for tumor cells [17] Adaptation to hypoxia in the tumor microenvironment is critical for survival and metastatic potential. PERK has also been shown to promote cancer proliferation by limiting oxidative DNA damage and death [18, 19] Moreover, a newly identified PERK inhibitor has been shown to have antitumor activity in a human pancreatic tumor xenograft model [20] Compounds disclosed herein decrease the viability of cells that are subjected to ER-stress. Thus, pharmacological and acute inhibition of the PERK branch with the compounds disclosed herein results in reduced cellular fitness. During tumor growth, compounds disclosed herein, that block the cytoprotective effects of elF2a phosphorylation upon stress may prove to be potent anti-proliferative agents.

It is known that under certain stress conditions several elF2a kinases can be simultaneously activated. For example, during tumor growth, the lack of nutrients and hypoxic conditions are known to both activate GCN2 and PERK. Like PERK, GCN2 and their common target, ATF4, have been proposed to play a cytoprotective role [21] By blocking signaling by both kinases, compounds disclosed herein may bypass the ability of the ISR to protect cancer cells against the effects of low nutrients and oxygen levels encountered during the growth of the tumor. Prolonged ER stress leads to the accumulation of CHOP, a pro-apoptotic molecule. In a prion mouse model, overexpression of the phosphatase of elF2a increased survival of prion- infected mice whereas sustained elF2a phosphorylation decreased survival [22] The restoration of protein translation rates during prion disease was shown to rescue synaptic deficits and neuronal loss. The compounds disclosed herein th at make cells insensitive to elF2a phosphorylation sustain protein translation. Compounds disclosed herein could prove potent inhibitors of neuronal cell death in prion disease by blocking the deleterious effects of prolonged elF2a phosphorylation. Given the prevalence of protein misfolding and activation on the UPR in several neurodegenerative diseases (e.g. Alzheimer's (AD) and Parkinson's (PD)), manipulation of the PERK-elF2a branch could prevent synaptic failure and neuronal death across the spectrum of these disorders.

Another example of tissue-specific pathology that is linked to heightened elF2a phosphorylation is the fatal brain disorder, vanishing white matter disease (VWM) or childhood ataxia with CNS hypo-myelination (CACH). This disease has been linked to mutation in elF2B, the GTP exchange factor that is necessary for elF2 function in translation [23] elF2a phosphorylation inhibits the activity of elF2E3 and mutations in this exchange factor that reduce its exchange activity exacerbate the effects of elF2a phosphorylation. The severe consequences of the CACH mutations point to the dangers of UPR hyper-activation, especially as it pertains to the myelin-producing oligodendrocyte. Small molecules, such as compounds disclosed herein, that block signaling through elF2a phosphorylation may reduce the deleterious effects of its hyperactivation in VWM.

In another aspect is provided a method of improving long-term memory in a patient, the method including administering a therapeutically effective amount of a compound of Fo rm u l a (I) to the patient. In embodiments, the patient is human. In embodiments, the patient is a mammal.

In embodiments, the compounds set forth herein are provided as pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient. In embodiments of the method, the compound, or a pharmaceutically acceptable salt thereof, is co-adminstered with a second agent (e.g. therapeutic agent). In embodiments of the method, the compound, or a pharmaceutically acceptable salt thereof, is co-adminstered with a second agent (e.g. therapeutic agent), which is administered in a therapeutically effective amount. In embodiments, the second agent is an agent for improving memory. Induction of long-term memory (LTM) has been shown to be facilitated by decreased and impaired by increased elF2a phosphorylation. The data strongly support the notion that under physiological conditions, a decrease in elF2a phosphorylation constitutes a critical step for the long term synaptic changes required for memory formation and ATF4 has been shown to be an important regulator of these processes [24] [25] [26] It is not known what the contributions of the different elF2a kinases to learning is or whether each play a differential role in the different parts of the brain. Regardless of the elF2a kinase/s responsible for phosphorylation of elF2a in the brain, compounds disclosed herein th at block translation and ATF4 production make them ideal molecules to block the effects of this phosphorylation event on memory. Pharmacological treatment with compounds disclosed herein increase spatial memory and enhance auditory and contextual fear conditioning.

Regulators of translation, such as the compounds of Formula (I), could serve as therapeutic agents that improve memory in human disorders associated with memory loss such as Alzheimer's disease and in other neurological disorders that activate the UPR in neurons and thus could have negative effects on memory consolidation such as Parkinson's disease, Amyotrophic lateral sclerosis and prion diseases. In addition, a mutation in elF2y, that disrupts complex integrity linked intellectual disability (intellectual disability syndrome or ID) to impaired translation initiation in humans [27] Hence, two diseases with impaired elF2 function, ID and VWM, display distinct phenotypes but both affect mainly the brain and impair learning.

The compounds of Formula (I) are also useful in applications where increasing protein production output is desirable, such as in vitro cell free systems for protein production. In vitro systems have basal levels of elF2a phosphorylation that reduce translational output [28, 29] Similarly, production of antibodies by hybridomas may also be improved by addition of compounds disclosed herein.

In another aspect is provided a method of increasing protein expression of a cell or in vitro expression system, the method including administering an effective amount of a compound of Formula (I) to the cell or expression system. In embodiments, the method is a method of increasing protein expression by a cell and includes administering an effective amount of a compound of Formula (I) to the cell. In embodiments, the method is a method of increasing protein expression by an in vitro protein expression system and includes administering an effective amount of a compound of Formula (I) to the in vitro (e.g. cell free) protein expression system. In embodiments, the compounds set forth herein are provided as pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient. In embodiments of the method, the compound, or a pharmaceutically acceptable salt thereof, is co-adminstered with a second agent. In embodiments of the method, the compound, or a pharmaceutically acceptable salt thereof, is co-adminstered with a second agent, which is administered in a therapeutically effective amount. In embodiments, the second agent is an agent for improving protein expression.

Suitably, the present invention relates to a method for treating or lessening the severity of breast cancer, including inflammatory breast cancer, ductal carcinoma, and lobular carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of colon cancer.

Suitably the present invention relates to a method for treating or lessening the severity of pancreatic cancer, including insulinomas, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, and glucagonoma.

Suitably the present invention relates to a method for treating or lessening the severity of skin cancer, including melanoma, including metastatic melanoma.

Suitably the present invention relates to a method for treating or lessening the severity of lung cancer including small cell lung cancer, non-small cell lung cancer, squamous cell carcinoma, adenocarcinoma, and large cell carcinoma.

Suitably the present invention relates to a method for treating or lessening the severity of cancers selected from the group consisting of brain (gliomas), glioblastomas, astrocytomas, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, Wilm's tumor, Ewing's sarcoma, Rhabdomyosarcoma, ependymoma, medulloblastoma, head and neck, kidney, liver, melanoma, ovarian, pancreatic, adenocarcinoma, ductal adenocarcinoma, adenosquamous carcinoma, acinar cell carcinoma, glucagonoma, insulinoma, prostate, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy-cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, plasmacytoma, Immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma, megakaryoblastic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkins lymphoma, non- hodgkins lymphoma, lymphoblastic T cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, renal cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular cancer, gastric cancer, nasopharangeal cancer, buccal cancer, cancer of the mouth, GIST (gastrointestinal stromal tumor), neuroendocrine cancers and testicular cancer.

Suitably the present invention relates to a method for treating or lessening the severity of pre-cancerous syndromes in a mammal, including a human, wherein the pre- cancerous syndrome is selected from: cervical intraepithelial neoplasia, monoclonal gammapathy of unknown significance (MGUS), myelodysplastic syndrome, aplastic anemia, cervical lesions, skin nevi (pre-melanoma), prostatic intraepithleial (intraductal) neoplasia (PIN), Ductal Carcinoma in situ (DCIS), colon polyps and severe hepatitis or cirrhosis.

Suitably the present invention relates to a method for treating or lessening the severity of neurodegenerative diseases/injury, such as Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation.

Suitably the present invention relates to a method for preventing organ damage during and after organ transplantation and in the transportation of organs for transplantation. The method of preventing organ damage during and after organ transplantation will comprise the in vivo administration of a compound of Formula (I). The method of preventing organ damage during the transportation of organs for transplantation will comprise adding a compound of Formula (I) to the solution housing the organ during transportation.

Suitably the present invention relates to a method for treating or lessening the severity of ocular diseases/angiogenesis. The method of treating or lessening the severity of ocular diseases/angiogenesis will comprise the in vivo administration of a compound of Formula (I). In embodiments of methods according to the invention, the disorder of ocular diseases, including vascular leakage can be: edema or neovascularization for any occlusive or inflammatory retinal vascular disease, such as rubeosis irides, neovascular glaucoma, pterygium, vascularized glaucoma filtering blebs, conjunctival papilloma; choroidal neovascularization, such as neovascular age-related macular degeneration (AMD), myopia, prior uveitis, trauma, or idiopathic; macular edema, such as post surgical macular edema, macular edema secondary to uveitis including retinal and/or choroidal inflammation, macular edema secondary to diabetes, and macular edema secondary to retinovascular occlusive disease (i.e. branch and central retinal vein occlusion); retinal neovascularization due to diabetes, such as retinal vein occlusion, uveitis, ocular ischemic syndrome from carotid artery disease, ophthalmic or retinal artery occlusion, sickle cell retinopathy, other ischemic or occlusive neovascular retinopathies, retinopathy of prematurity, or Eale's Disease; and genetic disorders, such as VonHippel-Lindau syndrome.

In some embodiments, the neovascular age-related macular degeneration is wet age-related macular degeneration. In other embodiments, the neovascular age-related macular degeneration is dry age-related macular degeneration and the patient is characterized as being at increased risk of developing wet age-related macular degeneration.

The methods of treatment of the invention comprise administering an effective amount of a compound according to Formula (I) or a pharmaceutically acceptable salt, thereof to a patient in need thereof.

The invention also provides a compound according to Formula (I) or a pharmaceutically-acceptable salt thereof for use in medical therapy, and particularly in therapy for: cancer, pre-cancerous syndromes, Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, C re utzfeldt- Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, in organ transplantation and arrhythmias. The invention also provides a compound according to Formula (III) or a pharmaceutically-acceptable salt thereof for use in preventing organ damage during the transportation of organs for transplantation. Thus, in further aspect, the invention is directed to the use of a compound according to Formula (III) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of a disorder characterized by activation of the UPR, such as cancer. The methods of treatment of the invention comprise administering a safe and effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof to a mammal, suitably a human, in need thereof.

As used herein, "treating", and derivatives thereof, in reference to a condition means: (1) to ameliorate or prevent the condition or one or more of the biological manifestations of the condition, (2) to interfere with (a) one or more points in the biological cascade that leads to or is responsible for the condition or (b) one or more of the biological manifestations of the condition, (3) to alleviate one or more of the symptoms or effects associated with the condition, or (4) to slow the progression of the condition or one or more of the biological manifestations of the condition.

The term "treating" and derivatives thereof refers to therapeutic therapy.

Therapeutic therapy is appropriate to alleviate symptions or to treat at early signs of disease or its progression. Prophylactic therapy is appropriate when a subject has, for example, a strong family history of neurodegenerative diseases. Prophylactic therapy is appropriate when a subject has, for example, a strong family history of cancer or is otherwise considered at high risk for developing cancer, or when a subject has been exposed to a carcinogen.

The skilled artisan will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to refer to the prophylactic administration of a drug to substantially diminish the likelihood or severity of a condition or biological manifestation thereof, or to delay the onset of such condition or biological manifestation thereof.

As used herein, "safe and effective amount" in reference to a compound of formula (I), or a pharmaceutically acceptable salt thereof, means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects (at a reasonable benefit/risk ratio) within the scope of sound medical judgment. A safe and effective amount of the compound will vary with the particular route of administration chosen; the condition being treated; the severity of the condition being treated; the age, size, weight, and physical condition of the patient being treated; the medical history of the patient to be treated; the duration of the treatment; the nature of concurrent therapy; the desired therapeutic effect; and like factors, but can nevertheless be routinely determined by the skilled artisan.

As used herein, "patient", and derivatives thereof refers to a human or other mammal, suitably a human. The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered by any suitable route of administration, including systemic administration. Systemic administration includes oral administration, and parenteral administration. Parenteral administration refers to routes of administration other than enteral, transdermal, or by inhalation, and is typically by injection or infusion. Parenteral administration includes intravenous, intramuscular, and subcutaneous injection or infusion.

The compounds of Formula (I) or pharmaceutically acceptable salts thereof may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. For example, doses may be administered one, two, three, or four times per day. Doses may be administered until the desired therapeutic effect is achieved or indefinitely to maintain the desired therapeutic effect. Suitable dosing regimens for a compound of the invention depend on the pharmacokinetic properties of that compound, such as absorption, distribution, and half- life, which can be determined by the skilled artisan. In addition, suitable dosing regimens, including the duration such regimens are administered, for a compound of the invention depend on the condition being treated, the severity of the condition being treated, the age and physical condition of the patient being treated, the medical history of the patient to be treated, the nature of concurrent therapy, the desired therapeutic effect, and like factors within the knowledge and expertise of the skilled artisan. It will be further understood by such skilled artisans that suitable dosing regimens may require adjustment given an individual patient's response to the dosing regimen or over time as individual patient needs change.

Additionally, the compounds of Formula (I) or pharmaceutically-acceptable salts thereof may be administered as prodrugs. As used herein, a "prodrug" of a compound of the invention is a functional derivative of the compound which, upon administration to a patient, eventually liberates the compound of the invention in vivo. Administration of a compound of the invention as a prodrug may enable the skilled artisan to do one or more of the following: (a) modify the onset of the compound in vivo; (b) modify the duration of action of the compound in vivo; (c) modify the transportation or distribution of the compound in vivo; (d) modify the solubility of the compound in vivo; and (e) overcome a side effect or other difficulty encountered with the compound. Where a -COOH or -OH group is present, pharmaceutically acceptable esters can be employed, for example methyl, ethyl, and the like for -COOH, and acetate maleate and the like for -OH, and those esters known in the art for modifying solubility or hydrolysis characteristics. The compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cancer or pre-cancerous syndromes.

By the term "co-administration" as used herein is meant either simultaneous administration or any manner of separate sequential administration of an ATF4 pathway inhibiting compound, as described herein, and a further active agent or agents, known to be useful in the treatment of cancer, including chemotherapy and radiation treatment. The term further active agent or agents, as used herein, includes any compound or therapeutic agent known to or that demonstrates advantageous properties when administered to a patient in need of treatment for cancer. Preferably, if the administration is not simultaneous, the compounds are administered in a close time proximity to each other. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered by injection and another compound may be administered orally.

Typically, any anti-neoplastic agent that has activity versus a susceptible tumor being treated may be co-administered in the treatment of cancer in the present invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Heilman (editors), 6 ^th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and antifolate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

Examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are chemotherapeutic agents. Suitably, the pharmaceutically active compounds of the invention are used in combination with a VEGFR inhibitor, suitably 5-[[4-[(2,3-dimethyl-2H-indazol-6- yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzenesulfonam ide, or a pharmaceutically acceptable salt, suitably the monohydrochloride salt thereof, which is disclosed and claimed in in International Application No. PCT/US01 /49367, having an International filing date of December 19, 2001 , International Publication Number W002/0591 10 and an International Publication date of August 1 , 2002, the entire disclosure of which is hereby incorporated by reference, and which is the compound of Example 69. 5-[[4-[(2,3-dimethyl- 2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbe nzenesulfonamide can be prepared as described in International Application No. PCT/US01/49367.

In one embodiment, the cancer treatment method of the claimed invention includes the co-administration a compound of Formula (I) and/or a pharmaceutically acceptable salt thereof and at least one anti-neoplastic agent, such as one selected from the group consisting of anti-microtubule agents, platinum coordination complexes, alkylating agents, antibiotic agents, topoisomerase II inhibitors, antimetabolites, topoisomerase I inhibitors, hormones and hormonal analogues, signal transduction pathway inhibitors, non-receptor tyrosine kinase angiogenesis inhibitors, immunotherapeutic agents, proapoptotic agents, cell cycle signaling inhibitors; proteasome inhibitors; and inhibitors of cancer metabolism.

"Chemotherapeutic" or "chemotherapeutic agent" is used in accordance with its plain ordinary meaning and refers to a chemical composition or compound having antineoplastic properties or the ability to inhibit the growth or proliferation of cells.

Additionally, the compounds described herein can be co-administered with conventional immunotherapeutic agents including, but not limited to, immunostimulants (e.g., Bacillus Calmette-Guerin (BCG), levamisole, interleukin-2, alpha-interferon, etc.), monoclonal antibodies (e.g., anti-CD20, anti-HER2, anti-CD52, anti-HLA-DR, and anti- VEGF monoclonal antibodies), immunotoxins (e.g., anti-CD33 monoclonal antibody- calicheamicin conjugate, anti-CD22 monoclonal antibody-pseudomonas exotoxin conjugate, etc.), and radioimmunotherapy (e.g., anti-CD20 monoclonal antibody conjugated to ^{1 1 1} 1n, ⁹⁰ Y, or ^{1 31} 1 , etc.).

In a further embodiment, the compounds described herein can be co-administered with conventional radiotherapeutic agents including, but not limited to, radionuclides such as ⁴⁷ Sc, ⁶⁴ C ⁶⁷ C, ⁸⁹ Sr, ⁸⁶ Y, ⁸⁷ Y, and ²¹² Bi, optionally conjugated to antibodies directed against tumor antigens. Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are anti-PD-L1 agents.

Anti-PD-L1 antibodies and methods of making the same are known in the art.

Such antibodies to PD-L1 may be polyclonal or monoclonal, and/or recombinant, and/or humanized.

Exemplary PD-L1 antibodies are disclosed in:

US Patent No. 8,217,149; 12/633,339;

US Patent No. 8,383,796; 13/091 ,936;

US Patent No 8,552,154; 13/120,406;

US patent publication No. 201 10280877; 13/068337;

US Patent Publication No. 20130309250; 13/892671 ;

WQ2Q13019906;

Q2013079174;

US Application No. 13/51 1 ,538 (filed August 7, 2012), which is the US National Phase of International Application No. PCT/US10/58007 (filed 2010);

and

US Application No. 13/478,51 1 (filed May 23, 2012).

Additional exemplary antibodies to PD-L1 (also referred to as CD274 or B7-H1) and methods for use are disclosed in US Patent No. 7,943,743; US20130034559,

WQ2Q14055897, US Patent No. 8,168.179; and US Patent No. 7,595,048. PD-L1 antibodies are in development as immuno-modulatory agents for the treatment of cancer.

In one embodiment, the antibody to PD-L1 is an antibody disclosed in US Patent No. 8,217,149. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Patent No. 8,217,149.

In another embodiment, the antibody to PD-L1 is an antibody disclosed in US Application No. 13/51 1 ,538. In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No. 13/51 1 ,538.

In another embodiment, the antibody to PD-L1 is an antibody disclosed in Application No. 13/478,51 1 . In another embodiment, the anti-PD-L1 antibody comprises the CDRs of an antibody disclosed in US Application No. 13/478,51 1 . In one embodiment, the anti-PD-L1 antibody is BMS-936559 (MDX-1 105). In another embodiment, the anti-PD-L1 antibody is MPDL3280A (RG7446). In another embodiment, the anti-PD-L1 antibody is MEDI4736.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are PD-1 antagonist.

"PD-1 antagonist" means any chemical compound or biological molecule that blocks binding of PD-L1 expressed on a cancer cell to PD-1 expressed on an immune cell (T cell, B cell or NKT cell) and preferably also blocks binding of PD-L2 expressed on a cancer cell to the immune-cell expressed PD-1 . Alternative names or synonyms for PD-1 and its ligands include: PDCD1 , PD1 , CD279 and SLEB2 for PD-1 ; PDCD1 L1 , PDL1 , B7H1 , B7-4, CD274 and B7-H for PD-L1 ; and PDCD1 L2, PDL2, B7- DC, Btdc and CD273 for PD-L2. In any embodiments of the aspects or embodiments of the present invention in which a human individual is to be treated, the PD-1 antagonist blocks binding of human PD-L1 to human PD-1 , and preferably blocks binding of both human PD-L1 and PD-L2 to human PD-1 . Human PD-1 amino acid sequences can be found in NCBI Locus No.: NP_005009. Human PD-L1 and PD-L2 amino acid sequences can be found in NCBI Locus No.: NP_054862 and NP_079515,

respectively.

PD-1 antagonists useful in the any of the aspects of the present invention include a monoclonal antibody (mAb), or antigen binding fragment thereof, which specifically binds to PD-1 or PD-L1 , and preferably specifically binds to human PD-1 or human PD-L1 . The mAb may be a human antibody, a humanized antibody or a chimeric antibody, and may include a human constant region. In some embodiments, the human constant region is selected from the group consisting of lgG1 , lgG2, lgG3 and lgG4 constant regions, and in preferred embodiments, the human constant region is an lgG1 or lgG4 constant region. In some embodiments, the antigen binding fragment is selected from the group consisting of Fab, Fab'-SH, F(ab')2, scFv and Fv fragments.

Examples of mAbs that bind to human PD-1 , and useful in the various aspects and embodiments of the present invention, are described in US7488802, US7521051 , US8008449, US8354509, US8168757, W02004/004771 ,

W02004/072286, W02004/056875, and US201 1 /0271358. Specific anti-human PD-1 mAbs useful as the PD-1 antagonist in any of the aspects and embodiments of the present invention include: MK-3475, a humanized lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 2, pages 161 -162 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 6; nivolumab, a human lgG4 mAb with the structure described in WHO Drug Information, Vol. 27, No. 1 , pages 68-69 (2013) and which comprises the heavy and light chain amino acid sequences shown in Figure 7; the humanized antibodies h409A1 1 , h409A16 and h409A17, which are described in WO2008/156712, and AMP-514, which is being developed by Medimmune.

Other PD-1 antagonists useful in the any of the aspects and embodiments of the present invention include an immunoadhesin that specifically binds to PD-1 , and preferably specifically binds to human PD-1 , e.g., a fusion protein containing the extracellular or PD-1 binding portion of PD-L1 or PD-L2 fused to a constant region such as an Fc region of an immunoglobulin molecule. Examples of immunoadhesion molecules that specifically bind to PD-1 are described in WO2010/027827 and

WO2011/066342. Specific fusion proteins useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include AMP-224 (also known as B7-DCIg), which is a PD-L2-FC fusion protein and binds to human PD- 1 .

Other examples of mAbs that bind to human PD-L1 , and useful in the treatment method, medicaments and uses of the present invention, are described in

WO2013/019906, W02010/077634 A1 and US8383796. Specific anti-human PD-L1 mAbs useful as the PD-1 antagonist in the treatment method, medicaments and uses of the present invention include MPDL3280A, BMS-936559, MEDI4736, MSB0010718C.

KEYTRUDA/pembrolizumab is an anti-PD-1 antibody marketed for the treatment of lung cancer by Merck. The amino acid sequence of pembrolizumab and methods of using are disclosed in US Patent No. 8,168,757.

Opdivo/nivolumab is a fully human monoclonal antibody marketed by Bristol Myers Squibb directed against the negative immunoregulatory human cell surface receptor PD-1 (programmed death-1 or programmed cell death-1/PCD-1) with immunopotentiation activity. Nivolumab binds to and blocks the activation of PD-1 , an Ig superfamily transmembrane protein, by its ligands PD-L1 and PD-L2, resulting in the activation of T-cells and cell-mediated immune responses against tumor cells or pathogens. Activated PD-1 negatively regulates T-cell activation and effector function through the suppression of P13k/Akt pathway activation. Other names for nivolumab include: BMS-936558, MDX-1106, and ONO-4538. The amino acid sequence for nivolumab and methods of using and making are disclosed in US Patent No. US

8 008.449.

Additional examples of a further active ingredient or ingredients (anti-neoplastic agent) for use in combination or co-administered with the presently invented ATF4 pathway inhibiting compounds are immuno-modulators.

As used herein“immuno-modulators” refer to any substance including monoclonal antibodies that affects the immune system. The ICOS binding proteins of the present invention can be considered immune-modulators. Immuno-modulators can be used as anti-neoplastic agents for the treatment of cancer. For example, immune-modulators include, but are not limited to, anti-CTLA-4 antibodies such as ipilimumab (YERVOY) and anti-PD-1 antibodies (Opdivo/nivolumab and Keytruda/pembrolizumab). Other immuno- modulators include, but are not limited to, OX-40 antibodies, PD-L1 antibodies, LAG3 antibodies, TIM-3 antibodies, 41 BB antibodies and GITR antibodies.

Yervoy (ipilimumab) is a fully human CTLA-4 antibody marketed by Bristol Myers Squibb. The protein structure of ipilimumab and methods are using are described in US Patent Nos. 6,984,720 and 7,605,238.

Suitably, the compounds of the invention are combined with an inhibitor of the activity of the protein kinase R (PKR)-like ER kinase, PERK.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of neurodegenerative diseases/injury.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of diabetes.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of cardiovascular disease.

Suitably, the compounds of Formula (I) and pharmaceutically acceptable salts thereof may be co-administered with at least one other active agent known to be useful in the treatment of ocular diseases. The compounds described herein can be used in combination with one another, with other active agents known to be useful in treating cancer (e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers of secretory cells), neurodegenerative diseases, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, and/or intellectual disability syndromes (e.g. associated with impaired function of elF2 or components in a signal transduction pathway including elF2), or with adjunctive agents that may not be effective alone, but may contribute to the efficacy of the active agent.

In embodiments, the compounds set forth herein are provided as pharmaceutical compositions including the compound and a pharmaceutically acceptable excipient. In embodiments of the method, the compound, or a pharmaceutically acceptable salt thereof, is co- adminstered with a second agent (e.g. therapeutic agent). In embodiments of the method, the compound, or a pharmaceutically acceptable salt thereof, is co-adminstered with a second agent (e.g. therapeutic agent), which is administered in a therapeutically effective amount. In embodiments of the method, the second agent is an agent for treating cancer (e.g. pancreatic cancer, breast cancer, multiple myeloma, or cancers of secretory cells), neurodegenerative diseases, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, and/or intellectual disability syndromes (e.g. associated with impaired function of elF2 or components in a signal transduction pathway including elF2), or an inflammatory disease (e.g. POCD or TBI). In embodiments, the second agent is an anti-cancer agent. In embodiments, the second agent is a chemotherapeutic. In embodiments, the second agent is an agent for improving memory. In embodiments, the second agent is an agent for treating a neurodegenerative disease. In embodiments, the second agent is an agent for treating vanishing white matter disease. In embodiments, the second agent is an agent for treating childhood ataxia with CNS hypo- myelination. In embodiments, the second agent is an agent for treating an intellectual disability syndrome. In embodiments, the second agent is an agent for treating pancreatic cancer. In embodiments, the second agent is an agent for treating breast cancer. In embodiments, the second agent is an agent for treating multiple myeloma. In embodiments, the second agent is an agent for treating myeloma. In embodiments, the second agent is an agent for treating a cancer of a secretory cell. In embodiments, the second agent is an agent for reducing elF2a phosphorylation. In embodiments, the second agent is an agent for inhibiting a pathway activated by elF2a phosphorylation. In embodiments, the second agent is an agent for inhibiting the integrated stress response. In embodiments, the second agent is an anti-inflammatory agent.

The term "elF2alpha" or "elF2a" refers to the protein "Eukaryotic translation initiation factor 2A". In embodiments, "elF2alpha" or "elF2a" refers to the human protein. Included in the term "elF2alpha" or "elF2a" are the wildtype and mutant forms of the protein. In embodiments, "elF2alpha" or "elF2a" refers to the protein associated with Entrez Gene 83939, OMIM 609234, UniProt Q9BY44, and/or RefSeq (protein) NP 114414.

Suitably, the present invention relates to a method for treating an integrated stress response associated disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.

Suitably, the integrated stress response-associated disease is cancer. Suitably, the integrated stress response-associated disease is a neurodegenerative disease. Suitably, the integrated stress response-associated disease is vanishing white matter disease. Suitably, the integrated stress response-associated disease is childhood ataxia with CNS hypo-myelination. Suitably, the integrated stress response-associated disease is an intellectual disability syndrome.

Suitably, the present invention relates to a method for treating a disease associated with phosphorylation of elF2a in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient.

Suitably, the disease associated with phosphorylation of elF2 a is cancer. Suitably, the disease associated with phosphorylation of elF2 a is a neurodegenerative disease. Suitably, the disease associated with phosphorylation of elF2 a is vanishing white matter disease. Suitably, the disease associated with phosphorylation of elF2 a is childhood ataxia with CNS hypo-myelination. Suitably, the disease associated with phosphorylation of elF2 a is an intellectual disability syndrome.

Suitably, the present invention relates to a method for treating a disease selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome.

Suitably, the present invention relates to a method for treating an inflammatory disease in a patient in need of such treatment, the method including administering a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the patient. Suitably, the inflammatory disease is associated with neurological inflammation. Suitably, the inflammatory disease is postoperative cognitive dysfunction. Suitably, the inflammatory disease is traumatic brain injury or chronic traumatic encephalopathy (CTE).

In embodiments of the method of treating a disease, the disease is selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypo-myelination, and an intellectual disability syndrome. In embodiments of the method of treating a disease, the disease is cancer. In embodiments of the method of treating a disease, the disease is a neurodegenerative disease. In embodiments of the method of treating a disease, the disease is vanishing white matter disease. In embodiments of the method of treating a disease, the disease is childhood ataxia with CNS hypo-myelination. In embodiments of the method of treating a disease, the disease is an intellectual disability syndrome. In embodiments of the method of treating a disease, the disease is associated with phosphorylation of elF2a. In embodiments of the method of treating a disease, the disease is associated with an elF2a signaling pathway. In embodiments of the method of treating a disease, the disease is a cancer of a secretory cell type. In embodiments of the method of treating a disease, the disease is pancreatic cancer. In embodiments of the method of treating a disease, the disease is breast cancer. In embodiments of the method oftreating a disease, the disease is multiple myeloma. In embodiments of the method of treating a disease, the disease is lymphoma. In embodiments of the method of treating a disease, the disease is leukemia. In embodiments of the method of treating a disease, the disease is a hematopoietic cell cancer.

In embodiments of the method of treating a disease, the disease is Alzheimer's disease. In embodiments of the method of treating a disease, the disease is Amyotrophic lateral sclerosis. In embodiments of the method of treating a disease, the disease is C re utzfeldt- Jakob disease. In embodiments of the method of treating a disease, the disease is frontotemporal dementia. In embodiments of the method of treating a disease, the disease is Gerstmann-Straussler-Scheinker syndrome. In embodiments of the method of treating a disease, the disease is Huntington's disease. In embodiments of the method of treating a disease, the disease is HIV-associated dementia. In embodiments of the method of treating a disease, the disease is kuru. In embodiments of the method of treating a disease, the disease is Lewy body dementia. In embodiments of the method of treating a disease, the disease is Multiple sclerosis. In embodiments of the method of treating a disease, the disease is Parkinson's disease. In embodiments of the method of treating a disease, the disease is a Prion disease. In embodiments of the method of treating a disease, the disease is an inflammatory disease. In embodiments, the inflammatory disease is postoperative cognitive dysfunction. In embodiments, the inflammatory disease is traumatic brain injury. In embodiments, the inflammatory disease is arthritis. In embodiments, the inflammatory disease is rheumatoid arthritis. In embodiments, the inflammatory disease is psoriatic arthritis. In embodiments, the inflammatory disease is juvenile idiopathic arthritis. In embodiments, the inflammatory disease is multiple sclerosis. In embodiments, the inflammatory disease is systemic lupus erythematosus (SLE). In embodiments, the inflammatory disease is myasthenia gravis. In embodiments, the inflammatory disease is juvenile onset diabetes. In embodiments, the inflammatory disease is diabetes mellitus type 1 . In embodiments, the inflammatory disease is Guillain-Barre syndrome. In embodiments, the inflammatory disease is Hashimoto's encephalitis. In embodiments, the inflammatory disease is Hashimoto's thyroiditis. In embodiments, the inflammatory disease is ankylosing spondylitis. In embodiments, the inflammatory disease is psoriasis. In embodiments, the inflammatory disease is Sjogren's syndrome. In embodiments, the inflammatory disease is vasculitis. In embodiments, the inflammatory disease is glomerulonephritis. In embodiments, the inflammatory disease is auto-immune thyroiditis. In embodiments, the inflammatory disease is Behcet's disease. In embodiments, the inflammatory disease is Crohn's disease. In embodiments, the inflammatory disease is ulcerative colitis. In embodiments, the inflammatory disease is bullous pemphigoid. In embodiments, the inflammatory disease is sarcoidosis. In embodiments, the inflammatory disease is ichthyosis. In embodiments, the inflammatory disease is Graves ophthalmopathy. In embodiments, the inflammatory disease is inflammatory bowel disease. In embodiments, the inflammatory disease is Addison's disease. In embodiments, the inflammatory disease is Vitiligo. In embodiments, the inflammatory disease is asthma. In embodiments, the inflammatory disease is allergic asthma. In embodiments, the inflammatory disease is acne vulgaris. In embodiments, the inflammatory disease is celiac disease. In embodiments, the inflammatory disease is chronic prostatitis. In embodiments, the inflammatory disease is inflammatory bowel disease. In embodiments, the inflammatory disease is pelvic inflammatory disease. In embodiments, the inflammatory disease is reperfusion injury. In embodiments, the inflammatory disease is sarcoidosis. In embodiments, the inflammatory disease is transplant rejection. In embodiments, the inflammatory disease is interstitial cystitis. In embodiments, the inflammatory disease is atherosclerosis. In embodiments, the inflammatory disease is atopic dermatitis. In embodiments, the method of treatment is a method of prevention. For example, a method of treating postsurgical cognitive dysfunction may include preventing postsurgical cognitive dysfunction or a symptom of postsurgical cognitive dysfunction or reducing the severity of a symptom of postsurgical cognitive dysfunction by administering a compound described herein prior to surgery.

In an embodiment, this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease selected from the group consisting of cancer, a neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome.

In an embodiment, this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of an integrated stress response associated disease.

In an embodiment, this invention provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease associated with phosphorylation of elF2a.

In an embodiment, this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease selected from the group consisting of cancer, a

neurodegenerative disease, vanishing white matter disease, childhood ataxia with CNS hypomyelination, and an intellectual disability syndrome..

In an embodiment, this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment an integrated stress response associated disease.

In an embodiment, this invention provides for the use of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of a disease associated with phosphorylation of elF2a.

Compositions

The pharmaceutically active compounds within the scope of this invention are useful as ATF4 pathway inhibitors in mammals, particularly humans, in need thereof. The present invention therefore provides a method of treating cancer, neurodegeneration and other conditions requiring ATF4 pathway inhibition, which comprises administering an effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof. The compounds of Formula (I) also provide for a method of treating the above indicated disease states because of their demonstrated ability to act as ATF4 pathway inhibitors. The drug may be administered to a patient in need thereof by any conventional route of administration, including, but not limited to, intravenous, intramuscular, oral, topical, subcutaneous, intradermal, intraocular and parenteral. Suitably, a ATF4 pathway inhibitor may be delivered directly to the brain by intrathecal or intraventricular route, or implanted at an appropriate anatomical location within a device or pump that continuously releases the ATF4 pathway inhibiting drug.

The pharmaceutically active compounds of the present invention are incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutical carriers are employed. Solid carriers include, starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Similarly, the carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies widely but, preferably, will be from about 25 mg to about 1 g per dosage unit. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid such as an ampoule, or an aqueous or nonaqueous liquid suspension.

The pharmaceutical compositions are made following conventional techniques of a pharmaceutical chemist involving mixing, granulating, and compressing, when necessary, for tablet forms, or mixing, filling and dissolving the ingredients, as appropriate, to give the desired oral or parenteral products.

Doses of the presently invented pharmaceutically active compounds in a pharmaceutical dosage unit as described above will be an efficacious, nontoxic quantity preferably selected from the range of 0.001 - 100 mg/kg of active compound, preferably 0.001 - 50 mg/kg. When treating a human patient in need of a ATF4 pathway inhibitor, the selected dose is administered preferably from 1 -6 times daily, orally or parenterally. Preferred forms of parenteral administration include topically, rectally, transdermally, by injection and continuously by infusion. Oral dosage units for human administration preferably contain from 0.05 to 3500 mg of active compound. Oral administration, which uses lower dosages, is preferred. Parenteral administration, at high dosages, however, also can be used when safe and convenient for the patient.

Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the particular ATF4 pathway inhibitor in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular patient being treated will result in a need to adjust dosages, including patient age, weight, diet, and time of administration.

When administered to prevent organ damage in the transportation of organs for transplantation, a compound of Formula (I) is added to the solution housing the organ during transportation, suitably in a buffered solution.

The method of this invention of inducing ATF4 pathway inhibitory activity in mammals, including humans, comprises administering to a subject in need of such activity an effective ATF4 pathway inhibiting amount of a pharmaceutically active compound of the present invention.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use as a ATF4 pathway inhibitor.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in therapy.

The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in treating cancer, pre-cancerous syndromes, Alzheimer’s disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, C re utzfeldt- Jakob Disease, and related prion diseases, progressive

supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. . The invention also provides for the use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for use in preventing organ damage during the transportation of organs for transplantation.

The invention also provides for a pharmaceutical composition for use as a ATF4 pathway inhibitor which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

The invention also provides for a pharmaceutical composition for use in the treatment of cancer which comprises a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

In addition, the pharmaceutically active compounds of the present invention can be co-administered with further active ingredients, such as other compounds known to treat cancer, or compounds known to have utility when used in combination with a ATF4 pathway inhibitor.

The invention also provides novel processes and novel intermedites useful in preparing the presently invented compounds.

The invention also provides a pharmaceutical composition comprising from 0.5 to 1 ,000 mg of a compound of Formula (I) or pharmaceutically acceptable salt thereof and from 0.5 to 1 ,000 mg of a pharmaceutically acceptable excipient.

Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following Examples are, therefore, to be construed as merely illustrative and not a limitation of the scope of the present invention in any way.

EXAMPLES

The following examples illustrate the invention. These examples are not intended to limit the scope of the present invention, but rather to provide guidance to the skilled artisan to prepare and use the compounds, compositions, and methods of the present invention. While particular embodiments of the present invention are described, the skilled artisan will appreciate that various changes and modifications can be made without departing from the spirit and scope of the invention. Example 1

Af.Ar-(pyridine-2.5-diyl)bis(2-(4-chlorophenoxy)acetamide )

Step 1 : To a 100-mL round bottom flask was added 2,5-diaminopyridine (99 mg, 0.907 mmol) and 2-(4-chlorophenoxy)acetic acid (389 mg, 2.086 mmol) in dichloromethane (DCM) (3 ml_), followed by triethylamine (0.632 ml_, 4.54 mmol) and T3P (1 .620 ml_, 2.72 mmol) (1 :50 PM). The resulting mixture was stirred at 23 °C for 18 h. The mixture was partitioned between EtOAc and water, then the organic phase was separated and washed with water and brine. It was dried over MgS0 ₄ , filtered, and concentrated in vacuo.

To the sample in DMSO (about 1 ml_) was added water (500 pL) to create a suspension. Acetonitrile was added (approximately 500 pl_) and the suspension was then heated; all solids went into solution. The solution was allowed to cool to room temperature where a precipitate formed. The precipitate was filtered and dried under vacuum overnight. N, IV- (pyridine-2, 5-diyl)bis(2-(4-chlorophenoxy)acetamide) (1 1 .0 mg, 0.025 mmol, 2.72 % yield) was recovered as a white solid. LCMS showed the desired mass ( m/z = 446.0 [M+H] ⁺ ).

¹ H NMR was consistent with the product. ¹ H NMR (400 MHz, DMSO-d ₆ ) d = 10.56 (s,

1 H), 10.28 (s, 1 H), 8.62 (s, 1 H), 8.05 - 7.97 (m, 2H), 7.41 - 7.31 (m, 4H), 7.09 - 6.96 (m, 4H), 4.79 (s, 2H), 4.73 (s, 2H). Example 2

N.N'-(pyrimidine-2.5-diyl)bis(2-(4-chlorophenoxy)acetamid e)

To a solution of pyrimidine-2, 5-diamine (300 mg, 2.72 mmol) in dimethyl sulfoxide (DMSO) (10 ml_), 2-(4-chlorophenoxy)acetyl chloride (1229 mg, 5.99 mmol) and TEA (2.278 ml_, 16.35 mmol) were added. The resulting mixture was stirred at 60 °C for 6 h. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with dichloromethane (3 x 30 ml_) and the organic layers were combined, washed with brine (2 x 20 ml_), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude product. The crude product was purifed by silica gel column chromatography and eluted with methanol/dichloromethane to afford the crude product. The crude product was poured into MeOH (10 mL) and filtered. The solid was washed with MeOH (3 x5 mL) and dried to afford the title compound as a light yellow solid (141 .3 mg, 95% pure, 12% yield). LCMS ESI m/z: 447 [M+H] ⁺ . ¹ HNMR (300MHz, DMSO-d6) d ppm: 10.79 (s, 1 H), 10.42 (s, 1 H), 8.89 (s, 2H), 7.28 -7.48 (m, 4H), 7.07 (m, 2H), 6.97 (m, 2H), 4.85 (s, 2H), 4.77 (s, 2H).

Example 3

N.N'-(thiophene-2.5-diyl)bis(2-(4-chlorophenoxy)acetamide )

Step 1 : tert-butyl (5-nitrothiophen-3-yl)carbamate

To a solution of 5-nitrothiophene-2-carboxylic acid (5 g, 28.9 mmol) in tert-butanol (50 ml_) was added DPPA (10.33 g, 37.5 mmol) and TEA (6.04 ml_, 43.3 mmol). The resulting mixture was stirred for 12 h at 85 °C. The reaction mixture was quenched with water (30 ml_). The resulting solution was extracted with Et ₂ 0(3 x 50 ml_) and the organic layers were combined, washed with brine (2 x 50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to afford the title compound as a brown solid (600 mg, 100% pure, 8.5% yield).

Step 2: tert-butyl (5-aminothiophen-2-yl)carbamate

To a solution of tert-butyl (5-nitrothiophen-3-yl)carbamate (600 mg, 2.456 mmol) in ethanol (10 ml_) was added iron (1372 mg, 24.56 mmol) and NH ₄ CI (aq) (5 ml_). The resulting mixture was stirred for 1 h at 50 °C. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with Et ₂ 0 (3 x 20 ml_) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product as a black solid (528mg). Used without further purification.

Step 3: tert-butyl (5-(2-(4-chlorophenoxy)acetamido)thiophen-2-yl)carbamate

To a solution of tert-butyl (5-aminothiophen-2-yl)carbamate (528 mg, 2.464 mmol) in dichloromethane (DCM) (15 mL) was added TEA (1 .030 mL, 7.39 mmol) and 2-(4- chlorophenoxy)acetyl chloride (606 mg, 2.96 mmol). The resulting mixture was stirred overnight at room temperature. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with dichloromethane (3 x 20 ml_) and the organic layers were combined, washed with brine (2 x 20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether and concentrated in vacuo to afford the title compound as a brown solid (103mg, 44% pure, 4.8% yield).

Step 4: N-(5-aminothiophen-2-yl)-2-(4-chlorophenoxy)acetamide

To a solution of tert-butyl (5-(2-(4-chlorophenoxy)acetamido)thiophen-2-yl)carbamate (103 mg, 0.269 mmol) in dichloromethane (DCM) (10 mL) and 4-methylmorpholine N-oxide (315 mg, 2.69 mmol) was added iodotrimethylsilane (0.220 mL, 1 .614 mmol) dropwise at 0 °C and stirred overnight at rt. The reaction mixture was concentrated under reduced pressure to afford crude product as a brown solid (76 mg). Used without further purification.

Step 5: N,N'-(thiophene-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide)

To a solution of N-(5-aminothiophen-2-yl)-2-(4-chlorophenoxy)acetamide (76 mg, 0.269 mmol) in dichloromethane (DCM) (15 mL) was added TEA (0.1 12 mL, 0.807 mmol) and 2- (4-chlorophenoxy)acetyl chloride (66.2 mg, 0.323 mmol). The resulting mixture was stirred for 2 h at rt. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to afford the crude product.The crude product was purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD Column, 5um,19*150mm ;Mobile Phase A:Water(10 M NH4HCO3), Mobile Phase B: ACN; Flow rate: 60ml_/min; Gradient: 45% B to 72.5% B in 5 9min; 254 nm; Rt: 8.23min) and concentrated in vacuo to provide the title compound as a pink solid (29.1 mg, 96% pure, 23% yield). LCMS ESI m/z: 451 [M+H] ⁺ . Ή NMR (300 MHz, CDCI3) d 8.61 (s, 2H), 7.32 (d, J= 8.7 Hz, 4H), 6.93 (d, J= 9.0Hz, 4H), 6.61 (s, 2H), 4.64 (s, 4H).

10 Compounds 4 to 5 are prepared generally according to the above Schemes and procedures described above for Example 2. Compound 5 was prepared as in Example 3 except that TFA replaced NMO/ TMSI in step 4.

Example 6

N.N'-(2.6-naphthyridine-1.4-diyl)bis(2-(4-chlorophenoxy)a cetamide)

Step 1 : 4-nitro-2,6-naphthyridin-1 -amine

To a solution of 2,6-naphthyridin-1 -amine (100 mg, 0.689 mmol) in H ₂ S0 ₄ (2 mL) at 0°C was added nitric acid (0.034 mL, 0.758 mmol). The reaction mixture was stirred for 16 h at rt. The pH of the solution was adjusted to 8 with saturated NaOH solution. The mixture was extracted with CHCI ₃ /iPrOH(3: 1)(3 x 20 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow solid (70 mg, 95% pure, 51 % yield). Step 2: 2, 6-naphthyridine-1 ,4-diamine

To a solution of 4-nitro-2,6-naphthyridin-1 -amine (320 mg, 1.683 mmol) in ethanol (8 ml_) and water (1 ml_) was added calcium chloride (187 mg, 1.683 mmol) and iron (470 mg, 8.41 mmol) at rt. The reaction mixture was stirred at 80 °C for 4 h.The reaction mixture was concentrated under reduced pressure. The resulting solution was extracted with ethyl acetate (5 x 20 ml_) and the organic layers were combined, washed with brine (1 x 10 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a yellow solid (250mg, 80% pure, 74%yield). Used without further purification.

Step 3: N,N'-(2,6-naphthyridine-1 ,4-diyl)bis(2-(4-chlorophenoxy)acetamide)

To a solution of 2, 6-naphthyridine-1 ,4-diamine (170 mg, 1.061 mmol) and triethylamine (537 mg, 5.31 mmol) in dichloromethane (DCM) (15 ml_) stirred at room temp was added 2-(4-chlorophenoxy)acetyl chloride (653 mg, 3.18 mmol). The reaction mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with dichloromethane (3 x 20 ml_) and the organic layers were combined, washed with brine (1 x 20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the residue. The residue was purified by silica gel column chromatography and eluted with methanol/dichloromethane to afford the crude product. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column 30*150mm, 5um ;Mobile Phase A:Water(10 M NH ₄ HCO ₃ +0.1 %NH ₃ .l-l ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 37% B to 57% B in 8 min; 254 nm; Rt: 7.72 min) and concentrated in vacuo to provide the title compound as a white solid (97.3 mg, 99.5% pure, 18.3%yield). LCMS ESI m/z: 497 [M+H] ⁺ . ¹ HNMR (300MHz, DMSO-d6) d ppm: 10.88 (br, 1 H), 10.52 (br, 1 H), 9.42 (s, 1 H), 8.72 (d, J= 5.7 Hz, 1 H), 8.59 (s, 1 H), 7.88 (d, J= 5.7 Hz, 1 H), 7.35 -7.38 (m, 4H), 7.04 -7.12 (m, 4H), 4.93 -4.96 (m, 4H).

Example 7

N.N'-(6-hvdroxypyridine-2.5-diyl)bis(2-(4-chlorophenoxy)a cetamide)

Step 1 : 6-methoxy-5-nitropyridin-2-amine

To a solution of 6-chloro-2-methoxy-3-nitropyridine (2g, 10.61 mmol) in tetrahydrofuran (THF) (50ml_) was added ammonia (50ml, 25.00 mmol) and stirred at room temp. The reation mixture was stirred at 100°C for 16h.The reaction was allowed to cool to room temperature and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether afford the title compound as a brown solid (1 .1 g, 78.6% pure, 48.2 % yield).

Step 2: 6-methoxypyridine-2, 5-diamine To a solution of 6-methoxy-5-nitropyridin-2-amine (900 mg, 5.32 mmol) in ethyl acetate (45mL) was added Pd/C (700 mg, 6.58 mmol ) and stirred at room temp under hydrogen (30psi). The reation mixture was stirred for 16h at room temp. The reation mixture was diluted with ethyl acetate. The resulting solution was filtered and the filter cake was washed with ethyl acetate. All filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to afford the title compound as a purple solid (750mg, 71 % pure, 72% yield).

Step 3: 3, 6-diaminopyridin-2-ol, Sodium bromide salt (N67543-65-A2)

6-Methoxypyridine-2, 5-diamine (700 mg, 5.03 mmol) was dissolved in hydrogen bromide (2035 mg, 25.2 mmol) and stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a brown solid (1 .4 g, 54% pure, 65.9% yield). Used without further purification.

Step 4: N,N'-(6-hydroxypyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acet amide)

To a solution of 3,6-diaminopyridin-2-ol (300 mg, 2.397 mmol) in tetrahydrofuran (THF) (5 mL) was added LiHMDS (1605 mg, 9.59 mmol) and 2-(4-chlorophenoxy)acetyl chloride (1229 mg, 5.99 mmol) at 0 °C.The reaction mixture was stirred for 16 h at room temp. The reaction mixture was quenched with water (15ml_). The resulting solution was extracted with dichloromethane (3 x 20 mL) and the organic layers were combined, washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the residue. The residue was purified by silica gel column chromatography and eluted with methanol/dichloromethane to afford the crude product. The crude product was purified by preparative HPLC Column: XBridge Shield RP18 OBD Column, 5um,19*150mm;Mobile Phase A:Water(10 M NH4HCO3), Mobile Phase B: ACN;

5 Flow rate: 25 mL/min; Gradient: 43% B to 60% B in 7 min; 254 nm; Rt: 6.67 min, and concentrated in vacuo to afford the title compound as a light grey solid (52.1 mg, 98% pure, 4.61 % yield). LCMS ESI, m/z: 462 [M+H] ⁺ . Ή NMR (300 MHz, DMSO-d6) 6:12.85 -10.01 (m, 1 H), 9.28 (s, 1 H), 8.23 (d, J= 8.4 Hz, 1 H), 7.36 -7.14 (m, 4H), 7.04 -6.40 (m, 4H), 6.59 (s, 1 H), 4.75 -4.48 (m, 4H).

10

Compound 8 is prepared generally according to the above Schemes and procedures described above for Example 7.

Table 2

15

Example 9

N.N'-(6-(1-hvdroxyethyl)pyridine-2.5-diyl)bis(2-(4-chloro phenoxy)acetamide)

Step 1 : 6-chloro-2-(1-ethoxyvinyl)-3-nitropyridine

To a solution of 2-bromo-6-chloro-3-nitropyridine (3g, 12.63 mmol) in acetonitrile (60 ml_) was added butyl(1 -ethoxyvinyl)-l2-stannane compound with octane (4.56 g, 12.63 mmol), PdCl2(PPh ₃ )2 (1 .330 g, 1 .895 mmol), and copper(l) iodide (0.120 g, 0.632 mmol) under nitrogen at room temperature. The reaction mixture was stirred at 60 °C for 6h. The reaction was allowed to cool to room temperature and filtered with diatomite. The filter cake was washed with acetonitrile and the organic layers were combined. The resulting solution was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether, and concentrated under reduced pressure to afford the title compound as a brown solid (2.8 g, 75% pure, 72.7% yield).

Step 2: 1 -(6-chloro-3-nitropyridin-2-yl)ethan-1-one

To a solution of 6-chloro-2-(1 -ethoxyvinyl)-3-nitropyridine (2.8 g, 12.25 mmol) in 1 ,4- dioxane (10 ml_) was added HCI (5 ml_, 12.25 mmol) at room temp. The reaction mixture was stirred at room temperature for 16h and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether, and concentrated under reduced pressure to afford the title compound as a yellow oil (1 .25 g, 94% pure, 47.8 % yield). Used without further purification.

Step 3: 1 -(6-amino-3-nitropyridin-2-yl)ethan-1 -one

A solution of 1 -(6-chloro-3-nitropyridin-2-yl)ethan-1 -one (1 g, 4.99 mmol) in ammonia (80 ml, 32.0 mmol, 0.4 M in 1 ,4-dioxane) was stirred for 16h at 90 °C. The reaction was allowed to cool to room temperature and concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether and concentrated under reduced pressure to afford the title compound as a yellow solid (780 mg, 92% pure, 79% yield).

Step 4: 1-(3,6-diaminopyridin-2-yl)ethan-1-ol

To a solution of 1 -(6-amino-3-nitropyridin-2-yl)ethan-1 -one (480 mg, 2.65 mmol) in methanol (50ml_) was added Pd/C (760mg, 7.14 mmol) and stirred at room temp under Hydrogen (30psi). The reaction mixture was stirred for 16h at room temp. The reaction mixture was diluted with ethyl acetate, filtered and the filter cake was washed with ethyl acetate. The filtrates were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to afford title compound as a purple solid (440 mg, 73% pure, 79% yield). Step 5: N,N'-(6-(1 -hydroxyethyl)pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide)

To a solution of 1 -(3,6-diaminopyridin-2-yl)ethan-1 -ol (200 mg, 1 .306 mmol) in N,N- Dimethylformamide (DMF) (20ml_) was added HATU (1340 mg, 3.53 mmol), DIEA (0.684 ml_, 3.92 mmol) and 2-(4-chlorophenoxy)acetic acid (731 mg, 3.92 mmol) at room temp. The reaction mixture was stirred at for 16h at rt. The reaction mixture was quenched with water (20ml_). The resulting solution was extracted with ethyl acetate (3 x 30 ml_) and the organic layers were combined, washed with brine (3 x 50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the residue. The residue was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether to afford the crude product. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column, 5um,19*150mm;Mobile Phase A:Water(10 M NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 40% B to 75% B in 12 min; 254 nm; Rt: 9.55 min) and concentrated in vacuo to provide the title compound as a white solid (42.1 mg, 99% pure, 6.51 % yield). LCMS ESI m/z 490 [M+H] ⁺ . Ή NMR (300 MHz, DMSO-d6) d 10.70 (s, 1 H), 10.51 (s, 1 H), 8.50 (d, J = 9.0 Hz, 1 H), 7.91 (d, J = 9.0 Hz, 1 H), 7.40 - 7.32 (m, 4H), 7.08 - 6.95 (m, 4H), 6.31 (d, J = 3.6 Hz, 1 H), 4.86 - 4.71 (m, 5H), 1 .32 (d, J = 6.6 Hz, 3H).

Compounds 10-11 are prepared generally according to the above Schemes and procedures described above for Example 9. Compound 10 was prepared as in Example 9 from 2-(6-chloro-3-nitropyridin-2-yl)ethan-1 -ol.

2-(6-chloro-3-nitropyridin-2-yl)ethan-1 -ol

To a solution of 6-chloro-2-methyl-3-nitropyridine (600 mg, 3.48 mmol) in dimethyl sulfoxide (DMSO) (10 ml_) stirred under nitrogen at room temperature was added formaldehyde (125 mg, 4.17 mmol) and benzyltrimethylammonium hydroxide (0.3 ml_, 1.650 mmol). The reaction mixture was stirred for 16h at 80°C. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with ethyl acetate (3 x20 ml_) and the organic layers were combined, washed with brine (1 x20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative MPLC with the following conditions: Column: Welch Ultimate XB C18 OBD Column, 60A, 40um,30*200mm; Mobile Phase A:Water, Mobile Phase B: ACN; Flow rate: 50 mL/min; Gradient: 15% B to 22% B in 10 min; 220 and 254 nm; Rt: 20.00 min to provide the title compound as a yellow solid (100 mg, 97% pure, 14% yield).

Table 3

Example 12

N.N'-(6-methylpyridine-2.5-diyl)bis(2-(4-chlorophenoxy)ac etamide)

Step 1 2-(4-chlorophenoxy)-N-(6-methyl-5-nitropyridin-2-yl)acetamid e

To a solution of 6-methyl-5-nitropyridin-2-amine (300 mg, 1 .959 mmol) in dichloromethane (DCM) (10 ml_) was added 2-(4-chlorophenoxy)acetyl chloride (402 mg, 1 .959 mmol) and TEA (0.819 ml_, 5.88 mmol). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with dichloromethane (3 x 20 ml_) and the organic layers were combined, washed with brine (2 x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by Prep-TLC. Mobile phase: 50% EtOAc/PE; Rf = 0.5 ; UV detection, to provide the title compound as a brown solid (400 mg, 95.8% pure, 63.5% yield).

Step 2: N-(5-amino-6-methylpyridin-2-yl)-2-(4-chlorophenoxy)acetamid e

To a solution of 2-(4-chlorophenoxy)-N-(6-methyl-5-nitropyridin-2-yl)acetamid e (400 mg, 1 .243 mmol) in ethyl acetate (20 mL) was added Pd-C (80 mg, 0.752 mmol). The resulting mixture was stirred for overnight under H ₂ (3 atm) at room temperature. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound as a yellow solid (285 mg, 62.8% pure, 49% yield). Used without further purification. Step 3: N,N ^, -(6-methylpyridine-2,5-diyl)bis(2-(4-chlorophenoxy)ace tamide)

To a solution of N-(5-amino-6-methylpyridin-2-yl)-2-(4-chlorophenoxy)acetamid e (140 mg, 0.480 mmol) in dichloromethane (DCM) (10 ml_) was added 2-(4-chlorophenoxy)acetyl chloride (148 mg, 0.720 mmol) and TEA (0.201 mL, 1.440 mmol). The resulting mixture was stirred at room temperature for 4 h. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 x20 mL) and the organic layers were combined, washed with brine (2 x20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by Prep-TLC. Mobile phase: 50% EtOAc/PE; Rf = 0.5; UV detection. The crude product was then purified by preparative HPLC (Column: XSelect CSH Prep C18 OBD Column, 5um,19*150mm ; Mobile Phase A : Water (10 M NH4HCO3), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 45% B to 65% B in 10 min; 254 nm; Rt: 9.55 min) and concentrated in vacuo to provide the title compound as a white solid (67.7 mg, 99% pure, 30% yield). LCMS ESI m/z 460 [M+H] ⁺ . ¹ HNMR (300MHz, Dimethyl sulfoxide-d6) d ppm: 10.57 (s, 1 H), 9.73 (s, 1 H), 7.88 (d, J = 8.4 Hz, 1 H), 7.72 (d, J = 8.4 Hz, 1 H), 7.22 - 7.50 (m, 4H), 6.84 - 7.18 (m, 4H), 4.77 (d, J = 11.1 Hz, 4H), 2.30 (s, 3H).

Compounds 13 to 16 are prepared generally according to the above Schemes and procedures described above for Example 12.

Compound 16 was prepared as in Example 12 except using LiHMDS/THF in place of TEA/DCM in the last step. Table 4

Example 17

2-(4-chlorophenoxy)-N-(6-(3-(4-chlorophenoxy)pyrrolidin-1 -yl)pyridin-3- vhacetamide

Step 1 : tert-butyl 3-(4-chlorophenoxy)pyrrolidine-1 -carboxylate

To a solution of tert-butyl 3-hydroxypyrrolidine-1 -carboxylate (10 g, 53.4 mmol) in tetrahydrofuran (THF) (250 mL) was added 4-chlorophenol (9.27 g, 72.1 mmol) ,PPh ₃ (16.81 g, 64.1 mmol) and the diisopropyl azodicarboxylate (DIDA) (12.96 g, 64.1 mmol) was added dropwise at 0°C in 30 min. The reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure, dissolved with DCM (300 mL) and the organic layers were washed with brine (3 x 300 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromotography and eluted with EtOAc/PE (0% ~ 7%) over 180 min. Pure fractions were combined and concentrated under reduced pressure to afford the title compound as a white solid (7.8 g, 26.1 mmol, 48.8 % yield), 99.6% pure. Step 2: 3-(4-chlorophenoxy)pyrrolidine

To a solution of tert-butyl 3-(4-chlorophenoxy)pyrrolidine-1 -carboxylate (400 mg, 1 .343 mmol) in 1 ,4-dioxane (2 mL) was added 4M HCI (6.0 mL, 24.00 mmol), at 0°C in 5 min. The reaction mixture was stirred at RT for 3h. The reaction mixture was concentrated under reduced pressure and quenched with 1 M NaOH (40 ml_).The resulting solution was extracted with dichloromethane (40 ml_x3), washed with brine (2 x 40 mL), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product as a yellow liquid (245 mg, 99% pure, 91 % yield). Used without further purification.

Step 3: 2-(4-chlorophenoxy)-N-(6-iodopyridin-3-yl)acetamide

To a solution of 6-iodopyridin-3-amine (1 .0 g, 4.55 mmol) in dichloromethane (DCM) (10 mL) was added Et ₃ N (3.17 mL, 22.73 mmol) and 2-(4-chlorophenoxy)acetyl chloride (1 .398 g, 6.82 mmol) stirred under nitrogen at 0 °C. The reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 x 30 mL) and the organic layers were combined, washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography, eluted with ethyl acetate/petroleum ether, and pure fractions were combined and concentrated under reduced pressure to afford the title compound as a white solid (1 .52 g, 96% purity, 83 % yield). Step 4: 2-(4-chlorophenoxy)-N-(6-(3-(4-chlorophenoxy)pyrrolidin-1 -yl)pyridin-3- yl)acetamide

To a solution of 2-(4-chlorophenoxy)-N-(6-iodopyridin-3-yl)acetamide (250 mg, 0.643 mmol) in 1 ,4-dioxane (10 ml_) was added 3-(4-chlorophenoxy)pyrrolidine (127 mg, 0.643 mmol), Cs ₂ C0 ₃ (419 mg, 1 .287 mmol), SPhos (26.4 mg, 0.064 mmol) and SPhos Pd G3 (55.7 mg, 0.064 mmol) stirred under nitrogen at room temperature. The reaction mixture was stirred overnight at 90 °C. The reaction mixture was quenched with water (30 ml_). The resulting solution was extracted with dichloromethane (3 x 50 ml_) and the organic layers were combined, washed with brine (2 x 30 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column 30x150mm 5um;Mobile Phase A:Water (10M NH4HCO3), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 50% B to 80% B in 10 min; 254 nm; Rt: 8.25 min) to provide the title compound as a white solid (14.6 mg, 98% pure, 4.85 % yield). LCMS ESI m/z 458 [M+H] ⁺ . ¹ HNMR (400 MHz, DMSO-d6) d ppm: 9.89 (s, 1 H), 8.24 - 8.25 (m, 1 H), 7.71 - 7.76 (m, 1 H), 7.33 - 7.38 (m, 4H), 6.99 - 7.05 (m, 4H), 6.49 - 6.53 (m, 1 H), 5.15 (s, 1 H), 4.66 (s, 2H), 3.67 - 3.73 (m, 1 H), 3.49 - 3.60 (m, 2H), 3.43 - 3.48 (m, 1 H), 2.24 - 2.37 (m, 1 H), 2.12 - 2.23 (m, 1 H).

Example 18

N.N'-(pyrimidine-2.5-diyl)bis(2-(4-chloro-3-fluorophenoxy )acetamide)

Step 1 2-(4-chloro-3-fluorophenoxy)acetyl chloride

To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (408 mg, 1 .994 mmol) in dichloromethane (DCM) (10 ml_) were added oxalyl chloride (0.209 ml_, 2.393 mmol) and DMF (0.015 mL, 0.199 mmol). The resulting mixture was stirred at rt for 2 h. The reaction mixture was concentrated under reduced pressure to afford the crude product as a yellow oil, 361 mg. Used without further purification.

Step 2: N-(2-aminopyrimidin-5-yl)-2-(4-chloro-3-fluorophenoxy)acetam ide

To a solution of 2-(4-chloro-3-fluorophenoxy)acetic acid (490 mg, 2.397 mmol) and pyrimidine-2, 5-diamine (220 mg, 1 .998 mmol) in N,N-Dimethylformamide (DMF) (10 mL) were added HATU (1 139 mg, 3.00 mmol) and DIEA (1 .047 mL, 5.99 mmol). The resulting mixture was stirred at 80 °C for overnight. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with EA (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by silica gel column chromatography and eluted with EA/PE. Pure fractions were combined and concentrated under reduced pressure to afford the title compound as a yellow solid (400mg, 95.2% pure, 64.2%yield).

Step 3: N,N'-(pyrimidine-2,5-diyl)bis(2-(4-chloro-3-fluorophenoxy)ac etamide)

To a solution of 2-(4-chloro-3-fluorophenoxy)acetyl chloride (361 mg, 1 .618 mmol) and N- (2-aminopyrimidin-5-yl)-2-(4-chloro-3-fluorophenoxy)acetamid e (400 mg, 1 .348 mmol) in N,N-dimethylformamide (DMF) (1 mL) was added NaH (108 mg, 2.70 mmol). The resulting mixture was stirred at 80 °C for overnight. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with EA (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The solid was washed by MeOH (2 X 10 mL) and the residue was dried to afford the title compound was isolated as a white solid (38.5 mg, 99.6% pure, 5.89% yield). LCMS ESI m/z 483 [M+H] ⁺ . ¹ HNMR (300MHz, DMSO-c/6) d ppm: 10.81 (s, 1 H), 10.42 (s, 1 H), 8.89 (s, 2H), 7.50 (m, 2H), 7.14 (m, 2H), 6.78 - 7.00 (m, 2H), 5.01 (s, 2H), 4.81 (s, 2H).

Example 19

N.N'-(4-methylpyrimidine-2.5-diyl)bis(2-(4-chlorophenoxy) acetamide)

Step 1 : 4-methylpyrimidine-2, 5-diamine A mixture of 5-bromo-4-methylpyrimidin-2-amine (2 g, 10.64 mmol), copper(ll) sulfate (0.2 g, 1 .253 mmol) and ammonium hydroxide (15 mL) was heated to 100 °C in a sealed tube and stirred for overnight. The reaction mixture was concentrated under reduced pressure to afford the crude product. The crude product was purified by silica gel column chromatography and eluted with methanol/dichloromethane. The desired fractions were combined and concentrated under reduced pressure to afford the title compound as a yellow solid (164 mg, 80% pure, 9.94% yield). Step 2: N,N'-(4-methylpyrimidine-2,5-diyl)bis(2-(4-chlorophenoxy)ace tamide)

To a solution of 4-methylpyrimidine-2, 5-diamine (100 mg, 0.805 mmol), N,N- dimethylformamide (DMF) (10 ml_), TEA (0.561 ml_, 4.03 mmol) and 2-(4- chlorophenoxy)acetyl chloride (495 mg, 2.416 mmol) was heated to 100 °C and stirred for 2 h, LCMS showed no SM remained. The reaction mixture was quenched with water (10 ml_). The resulting solution was extracted with ethyl acetate (3 x 20 ml_) and the organic layers were combined, washed with brine (2 x20 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column:

XBridge Prep C18 OBD Column, 5um,19*150mm; Mobile Phase A:Water(0.05%TFA), Mobile Phase B: ACN; Flow rate: 25 mL/min; Gradient: 42% B to 60% B in 7 min; 254 nm; Rt: 6.7 min) to provide the title compound as a white solid (31.2 mg, 99% pure, 8.3% yield). LCMS ESI m/z 461 [M+H] ⁺ . Ή NMR (300 MHz, Chloroform-d) d 10.76 (s, 1 H), 9.90 (s, 1 H), 8.53 (s, 1 H), 7.26 - 7.49 (m, 4H), 6.89 - 7.13 (m, 4H), 5.00 (s, 2H), 4.79 (s, 2H), 2.32 (s, 3H).

Example 20

N-(2-((4-chlorobenzyl)amino)quinazolin-6-yl)-2-(4-chlorop henoxy)acetamide

Step 1 : 6-bromo-N-(4-chlorobenzyl)quinazolin-2-amine

To a solution of 6-bromo-2-chloroquinazoline (200 mg, 0.821 mmol) in N,N- dimethylformamide (DMF) (1 mL) was added (4-chlorophenyl)methanamine (233 mg, 1 .643 mmol) and K ₂ C0 ₃ (341 mg, 2.464 mmol). The reaction mixture was stirred at 100 °C for 16h. The reaction mixture was cooled to rt and diluted with dichloromethane (50 mL). The mixture was filtered and concentrated under reduced pressure to afford crude product. The crude product was triturated with diethyl ether (20 mL). The mixture was filtered and the filter cake was washed with diethyl ether (20 mL). Then the filter cake was dried under vacuum to afford the title compound as a yellow solid (200 mg, 98% pure, 68% yield).

Step 2: tert-butyl (2-((4-chlorobenzyl)amino)quinazolin-6-yl)carbamate

To a solution of 6-bromo-N-(4-chlorobenzyl)quinazolin-2-amine (1 g, 2.87 mmol) in 1 ,4- dioxane (20 mL) stirred under nitrogen was added tert-butyl carbamate (0.672 g, 5.74 mmol), dicyclohexyl (2',4',6'-triisopropyl-[1 ,T-biphenyl]-2-yl)phosphane (0.273 g, 0.574 mmol), Cs ₂ C0 ₃ (1 .869 g, 5.74 mmol) and Pd ₂ (dba) ₃ (0.263 g, 0.287 mmol). The reaction mixture was stirred at 70 °C for 16h. The crude product was purified by silica gel column chromatography and eluted with ethyl acetate/petroleum ether. The desired fractions were concentrated under reduced pressure to afford the title compound as a yellow solid (150.0 mg, 87% pure, 1 1 .8% yield). Step 3: N2-(4-chlorobenzyl)quinazoline-2, 6-diamine

To a solution of tert-butyl (2-((4-chlorobenzyl)amino)quinazolin-6-yl)carbamate (150 mg, 0.390 mmol) in 1 ,4-dioxane (5 ml_) stirred was added HCI (0.118 ml_, 3.90 mmol) in 1 ,4- dioxane (5 ml_). The reaction mixture was stirred at rooom temp for 16h. The reaction mixture was concentrated under reduced pressure to afford the title compound as a yellow solid (100mg, 90% pure, 81 % yield). Used without further purification.

Step 4: N-(2-((4-chlorobenzyl)amino)quinazolin-6-yl)-2-(4-chlorophen oxy)acetamide

To a solution of N2-(4-chlorobenzyl)quinazoline-2, 6-diamine (100 mg, 0.351 mmol) in dichloromethane (DCM) (5 ml_) was added TEA (0.245 mL, 1.756 mmol) and 2-(4- chlorophenoxy)acetyl chloride (86 mg, 0.421 mmol). The reaction mixture was stirred at room temp for 5h. The reaction mixture was quenched with water (10 mL). The resulting solution was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative HPLC (Column: XBridge Shield RP18 OBD Column

30*150mm, 5um ;Mobile Phase A:Water(10 M NH ₄ HCO ₃ + 0.1 %NH ₃ .H ₂ O), Mobile Phase B: ACN; Flow rate: 60 mL/min; Gradient: 55% B to 70% B in 9 min; 220 nm; Rt: 8.80 min;lnjection Volumn:0.875 ml; Number Of Runs:5;) to afford the title compound as a white solid (16.7 mg, 98% pure, 10% yield). LCMS ESI m/z: 453 [M+H] ⁺ . ¹ H NMR (300 MHz,CDCI3) d ppm: 9.04 (s, 1 H), 8.36-8.31 (m, 2H), 7.70-7.62 (m, 2H), 7.38-7.30 (m,

5H), 7.03-6.93 (m, 2H), 4.78-4.76 (m, 2H), 4.66 (s, 2H), 2 amide NH not resolved. Example 21

N.N'-(3-methylpyrazine-2.5-diyl)bis(2-(4-chlorophenoxy)ac etamide)

Step 1 : tert-butyl (5-amino-6-methylpyrazin-2-yl)carbamate

To a solution of 5-bromo-3-methylpyrazin-2-amine (400 mg, 2.127 mmol) in 1 ,4-dioxane (20 ml_) was added potassium carbonate (588 mg, 4.25 mmol), tert-butyl carbamate (748 mg, 6.38 mmol), N,N'-dimethyl-1 ,2-ethanediamine (37.5 mg, 0.425 mmol) and Cul (40.5 mg, 0.213 mmol). The reaction mixture was heated to 100 °C and stirred for 16h. The reaction was allowed to cool to room temperature. The reaction mixture was quenched with water (100 ml_). The resulting solution was extracted with EtOAc (3 x 100 ml_) and the organic layers were combined, washed with brine (2 x 100 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product as a brown solid (400 mg, 70 % pure, 58% yield). Used without further purification.

Step 2: 3-methylpyrazine-2, 5-diamine To a solution of tert-butyl (5-amino-6-methylpyrazin-2-yl)carbamate (400 mg, 1 .784 mmol) in dichloromethane (DCM) (4 ml_) was added trifluoroacetic acid (TFA) (1 .0 ml_), then the reaction mixture was stirred at rt for 3h. The reaction mixture was concentrated under reduced pressure to afford the crude product as a brown solid (200 mg, 42% pure, 38% yield) . Used without further purification. LCMS ESI m/z: 125 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d6) d 7.84 (s, 2H), 7.72 (s, 1 H), 2.92 (d, J = 0.6 Hz, 6H), 2.77 (d, J = 0.8 Hz, 6H), 2.63 (s, 5H), 2.41 - 2.22 (m, 5H), 1 .60 (d, J = 2.3 Hz, 1 H), 1 .27 (s, 1 H).

Step 3: N,N'-(3-methylpyrazine-2,5-diyl)bis(2-(4-chlorophenoxy)aceta mide)

To a solution of 3-methylpyrazine-2, 5-diamine (200 mg, 1 .61 1 mmol) in N,N- dimethylformamide (DMF) (2 ml_) was added NaH (515 mg, 12.89 mmol) and 2-(4- chlorophenoxy)acetyl chloride (1321 mg, 6.44 mmol). The reaction mixture was heated to 80 °C and stirred for 3 days. The solution was cooled to rt. The reaction mixture was quenched with water (50 ml_). The resulting solution was extracted with EtOAc (3 x 50 ml_) and the organic layers were combined, washed with brine (2 x 50 ml_), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford crude product. The crude product was purified by preparative TLC (EA/PE = 1 :1 , Rt = 0.6), then triturated with MeOH (5 ml_) to provide the title compound as a white solid (31 .4 mg, 98% pure, 4% yield). LCMS ESI m/z: 461 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO-c/6) d ppm: 10.98 (s, 1 H), 10.43 (s, 1 H), 8.97 (s, 1 H), 7.33-7.38 (m, 4H), 6.98-7.04 (m, 4H), 4.83 (s, 2H), 4.79 (s, 2H), 2.33 (s, 3H).

Example 22

N.N'-(1.2.4.5-tetrazine-3.6-diyl)bis(2-(4-chlorophenoxy)a cetamide)

Step 1 : 1 ,2, 4, 5-tetrazine-3, 6-diamine

To a solution of 3,6-bis(3,5-dimethyl-1 H-pyrazol-1 -yl)-1 ,2,4,5-tetrazine (2 g, 7.40 mmol) in N-methyl-2-pyrrolidone (NMP) (5 mL) was added ammonia (0.480 mL, 22.20 mmol). The resulting mixture was stirred at 100 °C for overnight. The reaction was allowed to cool to room temperature. The reaction mixture was filtered and concentrated under reduced pressure to afford the title compound as a red solid (787 mg, 100% pure, 95% yield). Used without further purification.

Step 2: N,N'-(1 ,2,4,5-tetrazine-3,6-diyl)bis(2-(4-chlorophenoxy)acetamide)

To a solution of 1 ,2,4, 5-tetrazine-3, 6-diamine (200 mg, 1 .784 mmol) in N,N- dimethylformamide (DMF) (10 mL) was added 2-(4-chlorophenoxy)acetyl chloride (1097 mg, 5.35 mmol), 2-(3H-[1 ,2,3]triazolo[4,5-b]pyridin-3-yl)-1 ,1 ,3,3-tetramethylisouronium hexafluorophosphate(V) (2714 mg, 7.14 mmol) and N-ethyl-N-isopropylpropan-2-amine (1384 mg, 10.71 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was quenched with water (10ml_). The resulting solution was extracted with dichloromethane (3 x 10 mL) and the organic layers were combined, washed with brine (2 x 10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford the title compound as a red solid (233 mg, 97.14% pure, 28.2% yield). LCMS ESI m/z: 449 [M+H] ⁺ . ¹ HNMR (400MHz, DMSO) d ppm: 1 1 .87 (s, 2H), 7.34-7.36 (m, 4H), 6.99-7.01 (m, 4H), 4.99 (s, 4H).

Compounds 23 to 35 of Table 5 are prepared generally according to the above Schemes and procedures described above for Examples 1 to 22. Table 5.

Ġ 110

Example 36: ATF4 Cell Based Assay

The ATF4 reporter assay measures the effect of Thapsigargin induced cellular stress on ATF4 expression. For this reporter assay, a stable cell line was created by transfecting SH-SY5Y cells with a plasmid containing the NanoLuc® luciferase gene fused to the 5’-UTR of ATF4, under the control of the CMV promoter. The ATF4 5’-UTR contains two open reading frames which mediate the cellular stress-dependent translation of the reporter gene. Clones stably expressing the reporter construct were isolated and selected based on the luminescence response to thapsigargin and inhibition of this signal by test compounds. Briefly, SH-SY5Y-ATF4-NanoLuc cells were challenged with Thapsigargin for 14-18 hours to determine the stress effect with or without test compounds.

Cells were propagated in growth media consisting of 90% DMEM F12 (InVitrogen # 11320-033), 10% Fetal Bovine Serum (Gibco # 10438-026), 5mM Glutamax (Gibco #

35050-061), 5mM Hepes, (Gibco # 15630-080), and 0.5mg/ml Geneticin (Gibco # 10131- 027). Cells were prepared for the assay by removing all media from cells, washing the plated cells with phosphate buffered saline, and detached by adding a solution comprised of 10% Tryple express solution (lnVitrogen12604-021) and 90% enzyme-free cell dissociation buffer HANKS base (Gibco 13150-016). The trypsin was deactivated by adding assay media comprised of 90% phenol-red free DMEM F12 (InVitrogen, 11039), 10% Fetal Bovine Serum (Gibco # 10438-026), ( 5mM Glutamax (Gibco # 35050-061), 5mM Hepes, (Gibco # 15630-080), and 0.5mg/ml Geneticin (Gibco # 10131-027).

Suspended cells were spun down at 300g for 5 min, the supernatant was removed and the cell pellet was suspended in warm media (30-37°C) comprised as above but without 10% Fetal Bovine Serum to a concentration of 1 e6 cells/ml.

Assay plates were prepared by adding 250 nl_ of compound stock solution in 100% DMSO to each well, followed by dispensing 20 microliters/well cell suspension to deliver 15-20k cell/well. Cells were incubated for 1 hour at 37°C. Then, 5pL of 1 5pM or 1 pM of Thapsigargin (final concentration: 200-300nM) was added to each well of cells. Assay plates containing cells were incubated for 14-18 hours at 37°C.

The measurement of luciferase produced by the ATF4 constructs was measured as follows. Aliquots of the Nano-Glo reagent (Nano-Glo® Luciferase Assay Substrate, Promega, N1 13, Nano-Glo® Luciferase Assay Buffer, Promega, N1 12 (parts of Nano- Glo® Luciferase Assay System, N1 150) were brought to room temperature, the substrate and buffer were mixed according to manufacturer’s instructions. The cell plates were equilibrated to room temperature. 25microliters/well of the mixed Nano-Glo reagent were dispensed into assay wells and pulse spun to settle contents and the plate was sealed with film. The plates were incubated at room temperature for 1 hour before detecting luminescence on an Envision plate reader.

Example 37 - Capsule Composition

An oral dosage form for administering the present invention is produced by filing a standard two piece hard gelatin capsule with the ingredients in the proportions shown in Table 6, below.

Table 6

INGREDIENTS AMOUNTS

A/,A/-(pyridine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide ) 7 mg

(Compound of Example 1)

Lactose 53 mg

Talc 16 mg

Magnesium Stearate 4 mg

Example 38 - Injectable Parenteral Composition

An injectable form for administering the present invention is produced by stirring 1 .7% by weight of N,N'-(pyrimidine-2,5-diyl)bis(2-(4-chlorophenoxy)acetamide)

(Compound of Example 2) in 10% by volume propylene glycol in water. Example 39 Tablet Composition

The sucrose, calcium sulfate dihydrate and an ATF4 pathway inhibitor as shown in Table 7 below, are mixed and granulated in the proportions shown with a 10% gelatin solution. The wet granules are screened, dried, mixed with the starch, talc and stearic acid, screened and compressed into a tablet.

Table 7

INGREDIENTS AMOUNTS

N,N'-(thiophene-2,5-diyl)bis(2-(4- 12 mg

chlorophenoxy)acetamide) (Compound of Example 3) calcium sulfate dihydrate 30 mg sucrose 4 mg starch 2 mg talc 1 mg stearic acid 0.5 mg

Biological Activity

Compounds of the invention are tested for activity against ATF4 translation in the above assay. The compound of Example 1 was tested generally according to the above ATF4 cell based assay and in two experimental runs exhibited an ATF4 pathway inhibitory activity (plC50) of 7.64 and 7.57.

The compound of Example 2 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 250 nM.

The compound of Example 3 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 400 nM.

The compound of Examples 4-6, 9-10, 12,16, 21 and 22 were tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of between 1 and 10 mM.

The compound of Example 7 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 800 nM.

The compound of Example 8 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 250 nM.

The compound of Example 1 1 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 630 nM.

The compound of Example 13 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 500 nM.

The compound of Example 14 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 800 nM.

The compound of Example 15 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 800 nM.

The compound of Example 17 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 160 nM.

The compound of Example 18 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 400 nM.

The compound of Example 19 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 500 nM.

The compound of Example 20 was tested generally according to the above ATF4 cell based assay and in at least two experimental runs exhibited an average ATF4 pathway inhibitory activity (IC50) of 630 nM. References.

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While the preferred embodiments of the invention are illustrated by the above, it is to be understood that the invention is not limited to the precise instructions herein disclosed and that the right to all modifications coming within the scope of the following claims is reserved.