Methods of treatment for mitochondrial DNA depletion disorders

Abstract

Provided are methods of treating a subject having a Primary Mitochondrial Disorder (PMD) or Mitochondrial DNA Depletion Syndrome (MDDS) comprising administering a therapeutically effective amount of a compound listed in Table 1, Table 2, Table 3, Table 4, or Table 5, wherein the subject does not have a mutation in the DNA polymerase γ gene (POLG).

Description

Attorney Docket No. PTZ-012WOMETHODS OF TREATMENT FOR MITOCHONDRIAL DNA DEPLETION DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 742,727, filed January 7, 2025, the content of which is herein incorporated by reference in its entirety.BACKGROUND

[0002] Mitochondria have their own genome consisting of a variable copy number of a circular double-stranded molecule of DNA. In humans, mitochondrial DNA (mtDNA) is 16.5 kb and contains 37 genes encoding 13 proteins of the oxidative phosphorylation (OXPHOS) system, as well as 22 transfer RNAs (tRNAs) and 2 ribosomal RNAs (rRNAs) used for the translation of these proteins, which takes place within the mitochondria. Every cell contains several mitochondria and every mitochondrion in turn contains several copies of mtDNA. The amount of mitochondria and the mtDNA copy number depends on the tissue and its specific energy demands.

[0003] Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to abnormal OXPHOS. Mitochondrial disease is categorized into Primary (PMD) and Secondary Mitochondrial Diseases (SMD).

[0004] PMD is diagnosed clinically and ideally, but not always, confirmed by a known or pathogenic mtDNA or nuclear DNA (nDNA) mutation. The PMD genes either encode OXPHOS proteins directly or they affect OXPHOS function by impacting production of the complex machinery needed to run the OXPHOS process. A subset of PMD, called Mitochondrial DNA depletion syndromes (MDDS), is generally characterized due to defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mtDNA replication (e.g., POLG and TWNK) or mitochondrial nucleotide synthesis (e.g., TK2, SUCLA2, SUCLG1, RRM2B, DGUOK, and TYMP).

[0005] SMD can accompany many pathologic processes not involving OXPHOS, including inherited diseases with mutations in non-OXPHOS genes. SMD can also be acquired from adverse environmental effects which can cause oxidative stress. The environmental effects-1- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOmay result in mtDNA alterations as seen in a variety of other processes adversely impacting mitochondria such as aging, inflammatory response, mitotoxic drugs, etc.

[0006] One form of MDDS is characterized by a mutation in the POLG gene. POLy is the polymerase that is responsible for replication and proof-reading of mtDNA. As the only known DNA polymerase in mitochondria, POLy is required for all replication and proofreading functions, and is the main source of errors produced in mtDNA. Mutations in POLG represent the most prevalent single-gene cause of MDDS.

[0007] Other forms of MDDS are characterized by nuclear gene mutations causing disfunction in mitochondrial nucleotide synthesis. In these diseases, POLy is fully functional. The replication machinery is thus also fully functional. However, mutations in genes encoding, e g., TK2, TP, DGUOK, RRM2B, SUCLA2, and SUCLG1, result in low mtDNA levels because these mutations create an imbalance in the nucleotide pool levels.

[0008] Once such mutation causing low mtDNA levels is a mutation in helicase gene TWNK, which encodes the TWINKLE mtDNA helicase. The TWINKLE helicase is the main helicase in mitochondria. The TWINKLE helicase is required for H-strand synthesis where it is involved in duplex unwinding and fork progression during mtDNA replication (See Peter, Bradley, and Maria Falkenberg. " TWINKLE and other human mitochondrial DNA helicases: structure, function and disease." Genes 11.4 (2020): 408).

[0009] Another mutation causing an imbalance in the nucleotide pool level is a mutation in the thymidine kinase 2 (TK2) gene. This gene encodes a protein known as thymidine kinase 2, a mitochondrial matrix protein that phosphorylates thymidine and deoxy cytidine nucleosides to generate deoxythymidine monophosphate (dTMP) and deoxy cytidine monophosphate (dCMP). dTMP and dCMP are converted to deoxynucleotide triphosphates (dNTPs) which are the building blocks of mitochondrial DNA and necessary to replicate the mitochondrial genome. A TK2 gene mutation results in a low pool of dNTPs resulting in inefficient mtDNA replisome activity (See, Quan, J., et al. " P. 60A retrospective study of the combination of pyrimidine nucleosides in patients with thymidine kinase 2 (TK2) deficiency." Neuromuscular Disorders 29 (2019): S58).

[0010] Yet another mutation causing an imbalance in the nucleotide pool level is a mutation in the Deoxyribonucleoside kinase gene (DGUOK) encodes deoxyguanosine kinase.-2- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WODGUOK mediates the phosphorylation of deoxyguanosine and deoxyadenosine into the corresponding nucleotides, deoxyguanosine monophosphate (dGMP) and deoxyadenosine monophosphate (dAMP), in mitochondria. DGUOK mutation unbalances the mitochondrial dNTP pool which can cause mtDNA synthesis breakdown causing mitochondrial DNA depletion. DGUOK mutations are the major causes of hepatocerebral form of MDDS, accounting for about 20% of all MDDS cases, and is most common genetic factor of hepatic MDDS See, Guo, Jingyi, et al. " A combined model of human iPSC-derived liver organoids and hepatocytes reveals ferroptosis in DGUOK mutant mtDNA depletion syndrome." Advanced Science 8.10 (2021): 2004680).

[0011] There is an ongoing need for therapeutics that treat Mitochondrial DNA (mtDNA) Depletion Syndrome (MDDS), where the subject does not have a mutation in the DNA polymerase y gene.SUMMARY OF THE INVENTION

[0012] According to one aspect of the present disclosure, encompassed is a method of treating a Mitochondrial DNA (mtDNA) Depletion Syndrome (MDDS) in a subject in need thereof, the method comprising: optionally identifying a subject diagnosed with, or at risk of developing, a MDDS; and administering a therapeutically effective amount of a compound of formula (I), (II), (III), (IV), or (V), or a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, wherein the subject does not have a mutation in the DNA polymerase y gene.

[0013] In one aspect, provided herein is a method of treating a Mitochondrial DNA (mtDNA) Depletion Syndrome (MDDS) in a subject in need thereof comprising optionally identifying a subject diagnosed with, or at risk of developing, a MDDS, and administering a therapeutically effective amount of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, wherein the subject does not have a mutation or deletion in the DNA polymerase y gene (POLG).

[0014] In one aspect, provided herein is a method of treating a Primary Mitochondrial Disorder (PMD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Table 1, Table 2, Table 3, Table 4, or-3- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5, or a pharmaceutically acceptable salt thereof, wherein the subject does not have a mutation or deletion in the DNA polymerase y gene (POLG).

[0015] In some embodiments, the subject has one or more of: mtDNA deletions, mtDNA mutations, impaired mitochondrial oxidative phosphorylation, impaired recycling of mtDNA nucleotides, a reduction in the amount of mtDNA, impaired mtDNA function, impaired replication of mtDNA, impaired mechanisms of mtDNA, unbalanced nucleotide pools, low processivity, a defect in DNA-binding function, decreased DNA-binding affinity, reduced catalytic efficiency, a reduction in thymidine kinase activity, a reduction in Twinkle helicase activity, a reduction in thymidine phosphorylase activity, a reduction in deoxyguanosine kinase activity, a reduction in Ribonucleotide reductase M2B activity, a reduction in ribonuclease Hl (RNASEH1) activity, a reduction in mitochondrial SSBP1 activity, a reduction in Mitochondrial Genome Maintenance Exonuclease 1 (MGME1) activity, a reduction in DNA2 nuclease / helicase activity, a reduction in adenine nucleotide translocase type 1 (ANTI) protein activity, a reduction in succinyl-CoA ligase (SUCL) activity, a reduction in MP VI 7 protein activity, a reduction in activity of ATP synthase enzyme, or any combination thereof.

[0016] In some embodiments, the subject has a mutation in a gene selected from the group consisting of thymidine kinase 2 (TK2), twinkle (TWNK or C10ORF2), Thymidine Phosphorylase (TYMP), Deoxyguanosine Kinase (DGUOK), Ribonucleotide Reductase Regulatory Subunit M2B (RRM2B), Ribonuclease Hl (RNASEH1), Single-Stranded DNA Binding Protein 1 (SSBP1), Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA Replication Helicase / Nuclease 2 (DNA2), Adenine Nucleotide Translocator 1 (ANTI; SLC25A4), Succinate-CoA Ligase GDP -Forming Subunit Alpha (SUCLG1), Succinate-CoA Ligase ADP -Forming Subunit Beta (SUCLA2), MPV17 Mitochondrial Inner Membrane Protein (MPV17), Mitochondrially Encoded ATP Synthase Membrane Subunit 6 (MT-ATP6), Mitochondrially Encoded tRNA Leucine 1 (MT-TL1), Mitochondrially Encoded tRNA Histidine (MT-TH), Mitochondrially Encoded tRNA Serine 1 (MT-TS1), OPA1 (OPA1 mitochondrial dynamin like GTPase), FBXL4 (F-box and leucine rich repeat protein 4), and AGK (acylglycerol kinase).-4- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0017] In some embodiments, the subject has a mutation in a gene selected from the group consisting of thymidine kinase 2 (TK2), twinkle (TWNK or C10ORF2), Thymidine Phosphorylase (TYMP), Deoxyguanosine Kinase (DGUOK), Ribonucleotide Reductase Regulatory Subunit M2B (RRM2B), Ribonuclease Hl (RNASEH1), Single-Stranded DNA Binding Protein 1 (SSBP1), Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA Replication Helicase / Nuclease 2 (DNA2), Adenine Nucleotide Translocator 1 (ANTI; SLC25A4), Succinate-CoA Ligase GDP -Forming Subunit Alpha (SUCLG1), Succinate-CoA Ligase ADP -Forming Subunit Beta (SUCLA2), MPV17 Mitochondrial Inner Membrane Protein (MPV17), Mitochondrially Encoded ATP Synthase Membrane Subunit 6 (MT-ATP6), Mitochondrially Encoded tRNA Leucine 1 (MT-TL1), Mitochondrially Encoded tRNA Histidine (MT-TH), and Mitochondrially Encoded tRNA Serine 1 (MT-TS1).

[0018] In some embodiments, the subject has a mutation in a gene selected from the group consisting of TK2, twinkle (TWNK or C10ORF2), TYMP, DGUOK, and RRM2B.

[0019] In some embodiments, the subject has a mutation in a gene selected from the group consisting of TK2, DGUOK, SUCLA2, SUCLG1, MPV17, RRM2B, and MGMEL

[0020] In some embodiments, the subject has unbalanced nucleotide pools.

[0021] In some embodiments, the subject has a mutation in the TK2 gene, and the MODS is thymidine kinase 2 deficiency (TK2D). In some embodiments, the subject has a mutation in the TWNKLE gene, and the PMD or MDDS is infantile onset spinocerebellar ataxia (IOSCA), ataxia neuropathy spectrum, infantile-onset spinocerebellar ataxia, or progressive external ophthalmoplegia. In some embodiments, the subject has a mutation in the TYMP gene, and the PMD or MDDS is mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). In some embodiments, the subject has a mutation in the DGUOK gene, and the PMD or MDDS is Deoxyguanosine kinase (DGUOK) deficiency. In some embodiments, the subject has a mutation in the RRM2B gene, and the PMD or MDDS is encephalomyopathic form with renal tubulopathy (RRM2B-MDDS). In some embodiments, the subject has a mutation in the RNASEH1 gene, and the PMD or MDDS is a mitochondrial DNA maintenance disorder, adult-onset mitochondrial encephalomyopathy, or type 1 diabetes.-5- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0022] In some embodiments, the subject has a mutation in the SSBP1 gene, and the PMD or MDDS is Optic Atrophy 13 With Retinal And Foveal Abnormalities or Cone-Rod Dystrophy 2. In some embodiments, the subject has a mutation in the MGME1 gene, and the PMD or MDDS is mitochondrial DNA depletion syndrome type 11 (MTDPS11). In some embodiments, the subject has a mutation in the DNA2 gene, and the PMD or MDDS is progressive muscular dystrophy, progressive myopathy, or mitochondrial DNA depletion syndrome due to impaired replication and repair mechanisms of the mitochondrial DNA.

[0023] In some embodiments, the subject has a mutation in the ANTI (SLC25A4) gene, and the PMD or MDDS is Progressive external ophthalmoplegia (PEO), Cardiomyopathy and skeletal myopathy, Mitochondrial DNA depletion syndrome 12A (MTDPS-12A), Bipolar disorder, exercise intolerance, hyperlactatemia, cataracts, arterial hypertension, depression, or scoliosis. In some embodiments, the subject has a mutation in the SUCLG1 gene, and the PMD or MDDS is SUCLG1 -related mitochondrial DNA (mtDNA) depletion syndrome. In some embodiments, the subject has a mutation in the SUCLA2 gene, and the PMD or MDDS is Mitochondrial DNA depletion syndrome or Pyruvate dehydrogenase El -alpha deficiency.

[0024] In some embodiments, the subject has a mutation in the MP VI 7 gene, and the PMD or MDDS is MPV17-related hepatocerebral mitochondrial DNA depletion syndrome. In some embodiments, the subject has a mutation in the MT-TL1 gene, and the PMD or MDDS is Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS).

[0025] In some embodiments, the subject has a mutation in the MT-TL1 gene, the MT-TH, the MT-TS1 gene, or any combination thereof, and the PMD or MDDS is Myoclonic Epilepsy and Ragged Red Fibres (MERRF). In some embodiments, the subject has a mutation in the MT-ATP6 gene, and the PMD or MDDS is neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

[0026] In some embodiments, administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof: results in upregulating levels of mitochondrial DNA (mtDNA) in the subject; results in dose-dependent increases in mtDNA production in the subject; improves mtDNA recovery following depletion in the subject; results in an increase in mtDNA production in the subject; results in an increase in-6- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOmtDNA copy number per cell in the subject; results in restoration of mtDNA levels in the subject, and related improvement in cellular function; results in an increase in mtDNA production in subject-derived fibroblasts; increases cellular respiration in the subject; results in an increase in cellular energy in the subject; results in improved mitochondrial oxidative phosphorylation in the subject; results in improved recycling of mtDNA nucleotides in the subject; results in improved mtDNA function in the subject; results in improved replication of mtDNA in the subject; results in improved mechanisms of mtDNA in the subject; shifts ATP production rate to favour oxidative phosphorylation in the subject; results in improved liver health for the subject; results in improved catalytic efficiency in the subject; results in an increase in thymidine kinase activity; results in an increase in Twinkle helicase activity; results in an increase in thymidine phosphorylase activity; results in an increase in deoxyguanosine kinase activity; results in an increase in Ribonucleotide reductase M2B activity; results in an increase in ribonuclease Hl (RNASEH1) activity; results in an increase in mitochondrial SSBP1 activity; results in an increase in Mitochondrial Genome Maintenance Exonuclease 1 (MGME1) activity; results in an increase in DNA2 nuclease / helicase activity; results in an increase in adenine nucleotide translocase type 1 (ANTI) protein activity; results in an increase in succinyl-CoA ligase (SUCL) activity; results in an increase in MP VI 7 protein activity; results in an increase in activity of ATP synthase enzyme; or any combination thereof.

[0027] In some embodiments, upregulation of healthy mtDNA in the subject occurs in multiple organs, including the brain.

[0028] In some embodiments, the mtDNA level in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, as compared to the mtDNA level present in the subject prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.-7- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0029] In some embodiments, an increase in the mtDNA level in the subject is measured using a clinically acceptable technique.

[0030] In some embodiments, the clinically acceptable technique is PCR, Quantitative PCR (qPCR), digital PCR (dPCR), genomic methods such as whole exome sequences (WES) and whole genome sequencing (WGS), Low pass whole genome sequencing (IpWGS), or any combination thereof.

[0031] In some embodiments, the processivity and / or activity of an enzyme or protein in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, as compared to activity of the enzyme prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, and the enzyme or protein is selected from the group consisting of Twinkle helicase, thymidine phosphorylase, deoxyguanosine kinase, Ribonucleotide reductase M2B, ribonuclease Hl (RNASEH1), mitochondrial SSBP1, Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA2 nuclease / helicase, adenine nucleotide translocase type 1 (ANTI) protein, succinyl-CoA ligase (SUCL), MP VI 7 protein, and ATP synthase enzyme.

[0032] In some embodiments, the improvement in the processivity or activity of the protein or enzyme in the subject is measured using a clinically acceptable technique.

[0033] In some embodiments, the mtDNA copy number per cell in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% as compared to the mtDNA copy number per cell present in the subject prior to-8- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOadministration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the improved liver health for the subject is determined by comparing the amount of liver enzymes and / or liver mtDNA in the subject prior to treatment and following treatment with the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof; identifying a decreased presence of liver disease markers in the subject prior to treatment and following treatment with the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof; or any combination thereof.

[0035] In some embodiments, the therapeutically effective amount of the compound is a dose ranging from about 5 mg up to about 2000 mg. In some embodiments, the therapeutically effective amount of the compound is a dose ranging from about 30 to about 1000 mg. In some embodiments, the therapeutically effective amount of the compound is a dose ranging from 5 mg / kg up to about 1000 mg / kg.

[0036] In some embodiments, the compound is administered once per day.

[0037] In some embodiments, the therapeutically effective amount of the compound is below the nonclinical no-observed-adverse-effect level (NOAEL).

[0038] In some embodiments, the PMD or MDDS is inherited.

[0039] In some embodiments, the therapeutically effective amount of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof improves one or more symptoms of the PMD or MDDS disorder.

[0040] In some embodiments, the improvement in the one or more symptoms is measured using a clinically acceptable method.

[0041] In some embodiments, the symptom is selected from the group consisting of muscle function, muscle weakness, muscle atrophy, hypotonia, dystonia, loss of muscle coordination, loss of motor skills, sensory ataxia, epilepsy, encephalopathy with seizures, involuntary movements, seizures, status epilepticus, epilepsia partialis continua, focal motor seizures, -9- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOgeneralised status epilepticus, refractory convulsive status epilepticus, progressive weakness of the extraocular muscles, bilateral symmetrical ptosis, ptosis, ataxia, parkinsonism, liver function, liver disease, hepatopathy, hepatic impairment, hypoglycaemia, hepatic steatosis, developmental delay, growth retardation, gastrointestinal issues, weight loss, nausea, vomiting, diarrhoea or persistent diarrhoea, cachexia related to gastrointestinal dysmotility, dysphagia, cerebellar ataxia, brain abnormalities, neurodevelopmental regression, myopathies, eye problems, ophthalmoplegia, cataracts, strabismus, optic atrophy, external ophthalmoplegia, hearing loss, sensorineural hearing impairment or deafness, cardiac problems, cardiomyopathies, heart disease, visual problems, retinopathy, renal dysfunction, renal disease, diabetes mellitus, proximal myopathy, encephalomyopathy, neuropathy, peripheral neuropathy, sensory neuropathy, distal myopathy, demyelinating neuropathy, neuropathic pain, exercise intolerance, lactic acidosis, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, hypoglycaemia, myoclonus, myopathy, depression, dysarthria, premature menopause, ragged-red muscle fibres, lipodystrophy, and any combination thereof.

[0042] In some embodiments, the symptom is ataxia or seizures.

[0043] In some embodiments, the subject is a pediatric patient, an adolescent or young adult, or an adult. In some embodiments, the pediatric patient is less than 12 years old.

[0044] In some embodiments, the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, is a POLg activator compound.

[0045] In some embodiments, the compound is present in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

[0046] In some embodiments, the compound or composition is administered orally, intrathecally, enterally, or intravenously.

[0047] In some embodiments, the compound is l-((S)-8-chlorochroman-4-yl)-3-(2-(l-hydroxyethyl)thiazol-4-yl)urea, or a pharmaceutically acceptable salt thereof.-10- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0048] In one embodiment, the compound of formula I, II, III, IV, or V or a compound of Table 1, Table 2, Table 3, Table 4, or Table 5 is a POLg activator compound.

[0049] In one embodiment, the POLg activator has a formula I:wherein:R1is selected from the group consisting of H, C1-C3 alkyl, Cl, F, and CN;R2is H or C1-C3 alkyl substituted with OH or OCH3;R3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH;R4is each independently H or C1-C4 alkyl;Z is selected from the group consisting of Ci-Ce alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl, wherein: (1) Ci-Ce alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH, SO2R5, aryl, heteroaryl, and aryl-heteroaryl, (2) cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, (3) heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3-C6 cycloalkyl, C(O)CH, C(O)O-Ci-C3 alkyl, C(O)NR5R5, SO2-C1-C3 alkyl, and C1-C4 alkyl that is optionally substituted with OH, (4) aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R5, C3-C6 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7, R6R7, SO2R5, SO2NR5R5, and 4- or 6-membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group -11- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOconsisting of F, Cl, OR5, CN, C1-C4 alkyl, andNR5R5, (5) heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, OXO, SO2R5, and C1-C4 alkyl optionally substituted with a group selected from the group consisting of NR5R5, OR5, and C(O)NR5R5, (6) aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of chloro, fluoro, and C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of OH, O-C1-C3 alkyl, chloro, and fluoro; and (7) aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OH;R5is each independently H or C1-C4 alkyl;R6is H or Ci-Ce alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5;R7is H or C1-C5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1-C5 alkyl or CN, orR7is C1-C5 alkyl substituted with C3-C6 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5 alkyl, CN, NR5R5, and one or more fluoro, or R7is C3-C5 cycloalkyl optionally substituted with Ci alkyl optionally substituted with OH, orif R6and R7are attached to the same nitrogen atom, then R6and R7together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5 alkyl;n is 1-4;p is 1-2;with the proviso that a compound selected from the group consisting of:l-(l,5-dimethyl-IT / -pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea,l-(8-methylchroman-4-yl)-3-(l-(l-methylpiperidin-4-yl)-lJH-pyrazol-3-yl)urea,l-(l-(2-(dimethylamino)ethyl)-IT / -pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea,l-(l-( ec-butyl)-5 -methyl- IT / -pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, andl-(8-fluorochroman-4-yl)-3-(l-(pyridin-4-ylmethyl)-lJH-pyrazol-3-yl)urea, is excluded.

[0050] In one embodiment, the POLg activator has a formula (II):-12- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WORsFormula (II)wherein:Xi - X3 are independently carbon or nitrogen;Ri is independently selected from the group consisting of hydrogen, halogen, cyano, and OCH3;R2 is selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, C(O)ORe, C(0)NReR7, cycloalkyl, heterocyclyl, aryl, C(O)Re, ORe, and heterocyclodiene; wherein Ci-Ce alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(0)NReR7, SO2R6, ORe, heterocyclyl, cycloalkyl, NHC(O)Re, CF3, and NHS(O)(O)Re;wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of SO2R6, CCH3CH3NH2, NH2, and C3H5O;wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)Re and OH;wherein heterocyclodiene is optionally substituted with Ci-Ce alkyl;R3 is absent, hydrogen, C1-C4 alkyl, or halogen; wherein C1-C4 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)Re, halogen,or R2 and R3 are interconnected to form a five-member heteroatom ring;R4 and R5 are each independently absent or hydrogen;Rs is H, methyl, ethyl, C3-6 cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3;R7 is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; n is 1-4; and*denotes a chiral carbon.

[0051] In one embodiment, the POLG activator has a formula (III):-13- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOFormula (III)wherein:R1is selected from the group consisting of H, C1-C3 alkyl, Cl, F, CN, and O-Ci-Ce alkyl optionally substituted with one or more halogen;R2is H or C1-C3 alkyl optionally substituted with OR5;R3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH;R4is C-R5or S, wherein one R4is C-R5and the other R4is S;Z is selected from the group consisting of Ci-C6alkyl, Ci-C6alkene, NR5R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl-cycloalkyl, aryl -heterocyclyl, aryl -heteroaryl, and sulfonamide,wherein the (1) Ci-Ce alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, C(O)NR5R6, NR5R6, NR5-C(O)CH3, SO2R5, NH-SO2R5, heterocyclyl, aryl, heteroaryl, and aryl -heteroaryl, (2) cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, C1-C3 alkyl-OH, C1-C3 alkyl-O-Ci-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, (3) heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6 cycloalkyl, C(0)CH3, C(O)NR5R5, NH- C(O)R5, NH-SO2R5, and C1-C4 alkyl that is optionally substituted with one or more F or OH, (4) aryl is optionally substituted with one or more groups selected from the group consisting of: (i) C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R6, (ii) C3-C6 cycloalkyl that is-14- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOsubstituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and (iii) 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4 alkyl, oxo, and NR5R6, (5) heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR5R6, OR5, NR5R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and C1-C4 alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5R6, OR5, and C(O)NR5R6; (6) aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F; and (7) arylheteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5;R5is independently H or C1-C5 alkyl;R6is selected from the group consisting of H, cyclopropyl, and C1-C5 alkyl optionally substituted with one or more groups selected from the group consisting of NR5R5, OR5, and halogen;R7is cycloalkyl optionally substituted with one or more halogens; n is 1-4;p is 1-2;with the proviso that a compound selected from the group consisting of(k)-l-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-27 / -pyran-4-yl)thiazol-2-yl)urea, 1-(chroman-4-yl)-3-(4-cyclobutylthiazol-2-yl)urea,l-((3 / ,4 / )-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, andl-(5-cyclopropylthiazol-4-yl)-3-((3A,4A)-3-(hydroxymethyl)chroman-4-yl)urea, is excluded.

[0052] In one embodiment, the POLg activator has a formula (IV):-15- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOFormula (IV)wherein:A is thiazole, 2-pyridyl, pyrazole, oxazole, azaindole, substituted thiazole, substituted 2-pyridyl, substituted pyrazole, substituted oxazole, or substituted azaindole;Ri is hydrogen, halogen, Ci-Ce alkyl, substituted Ci-Ce alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;wherein A is connected to N via a C-N bond; and* denotes a chiral carbon.

[0053] In one embodiment, the POLg activator has a formula (V):wherein:A is substituted di azole, oxazole, substituted oxazole, thiazole, substituted thiazole, thiadi azole, substituted thiadi azole, oxadi azole, substituted oxadi azole, tri azole, substituted triazole, pyridine or substituted pyridine;wherein when the substituted diazole is a pyrazole, the substitution is not an unsubstituted phenyl.IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0054] In one embodiment, the POLg activator has a structure of formula (I), (II), (III), (IV), or (V), or as shown in any of Table 1, Table 2, Table 3, Table 4, or Table 5.

[0055] In one embodiment, the POLg activator is present in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

[0056] In one embodiment, the POLg activator or composition is administered orally, intrathecally, enterally, or intravenously.

[0057] Both the foregoing summary and the following brief description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details of the invention, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.BRIEF DESCRIPTION OF THE DRAWINGS

[0058] FIG. 1 graphically shows the classification of primary mitochondrial disorders, and supports that increasing and restoring mtDNA has broad application to improve human health. The smallest circle refers to POLy mutations, which lead to severe disease due to lack of mtDNA. These are the most common nuclear mutations in mitochondrial diseases. The next category is mtDNA Depletion Syndromes, where mutations in other nuclear- encoded proteins lead to severe disease due to lack of mtDNA. The next category is mtDNA Mutation / Deletion Syndromes, where Mutations & deletions in mtDNA lead to >70% of mitochondrial diseases.

[0059] FIG. 2 shows a graph of cells treated with ethidium bromide (EtBr) to deplete mtDNA (WT, i.e., healthy cells with a fully functional mtDNA replisome), time course (7-day depletion), with mtDNA / nDNA normalized to undepleted vs days (0 to 14). T7 = 7-day depletion in proliferation phase before compound treatment (dO). Proliferating WT cells did not show a different rate of mtDNA recovery when treated with DMSO compared to treatment with 1 pM of a POLg activator described herein. In proliferating WT, non-diseased cells (fully functional replisome with ample dNTP pools), POLG activity was not ratelimiting.-17- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0060] FIG. 3A-D demonstrate that treatment with POLg activators described herein accelerates mtDNA recovery relative to a control for patient fibroblasts with quiescent mutant MPV17 (FIG. 3A and FIG 3D), mutant RRM2B (FIG. 3B) or mutant DGOUK (FIG. 3C) (i.e., accelerated mtDNA recovery relative to a control).

[0061] FIGs. 4A & B show that the POLg activators described herein increase mtDNA copy number in the presence of TWINKLE (mtDNA helicase) mutations that lead to MDDS.

[0062] FIG. 5 shows that POLg activators described herein increase mtDNA copy number in the presence of TK2 mutations that cause MDDS.

[0063] FIGs. 6A and B show that the POLg activators described herein elicit positive pharmacology (e.g., improved liver health) in a DGUOK-KO mice model.

[0064] FIG. 7A and 7B show results of two independent experiments where POLg activator-treated TK2 KO mice lived longer and had more mtDNA copy number than vehicle-treated mice.

[0065] FIGs. 8A-8D show the mtDNA copy number of patient fibroblasts with TK2 or TYMP mutations associated with PMD treated with POLg activators described herein for 7 days and 14 days.

[0066] FIG. 9 shows the mtDNA copy number of wild-type neural stem cells (NCS) treated with a POLG activator described herein at the indicated concentrations.DETAILED DESCRIPTIONI. Overview

[0067] The present invention is directed to methods of treating a Primary Mitochondrial Disease (PMD) or Mitochondrial DNA (mtDNA) Depletion Syndrome (MDDS) comprising: administering a therapeutically effective amount of a compound as described herein to a subject in need thereof, where the subject does not have a mutation in the DNA polymerase y gene.

[0068] Primary mitochondrial diseases (PMDs)

[0069] Primary mitochondrial diseases (PMDs) are a heterogeneous group of genetic disorders caused by dysfunction of the mitochondria, which is responsible for energy-18- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOproduction through oxidative phosphorylation (OXPHOS). These diseases result from mutations in either mitochondrial DNA (mtDNA) or nuclear DNA genes that encode mitochondrial proteins essential for mitochondrial function. PMDs generally affect high-energy-demand organs such as the brain, heart, muscle, and liver. These disorders can affect multiple organ systems simultaneously and present with a wide spectrum of severity and age of onset. In the case of mtDNA mutations, the phenomenon of heteropl asmy — wherein the proportion of mutant versus wild-type mtDNA varies — significantly affects disease severity and clinical presentation.

[0070] POLG-related disorders (e.g., POLy-related disorders) represent a significant subset of PMDs caused by mutations in the POLG gene, some of which are listed in FIG. IB. These disorders include Alpers-Huttenlocher syndrome (Alpers syndrome), autosomal dominant progressive external ophthalmoplegia (adPEO), autosomal recessive progressive external ophthalmoplegia (arPEO), mitochondrial recessive ataxia syndrome (MIRAS), sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), spinocerebellar ataxia with epilepsy (SCAE), myocerebrophepatopathy syndrome (MCHS), and ataxianeuropathy syndrome. These conditions vary in their clinical symptoms but all have impaired mitochondrial DNA replication

[0071] Classical mitochondrial syndromes include Leigh syndrome (subacute necrotizing encephalomyelopathy), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibers (MERRF), Kearns-Sayre syndrome (KSS), chronic progressive external ophthalmoplegia (CPEO), Leber hereditary optic neuropathy (LHON), neuropathy, ataxia, and retinitis pigmentosa (NARP), and Pearson syndrome. Each of these syndromes is associated with specific mtDNA mutations or deletions.

[0072] Mitochondrial DNA depletion syndromes (MDDs) represent a category of PMDs characterized by a severe reduction in mtDNA copy number in affected tissues. The severity of mtDNA depletion often correlates with disease progression and clinical outcome.

[0073] Additional categories of PMDs include mitochondrial translation defects, such as combined oxidative phosphorylation deficiency (COXPD) disorders and mitochondrial aminoacyl-tRNA synthetase deficiencies; disorders of mitochondrial dynamics, including-19- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOCharcot-Marie-Tooth disease type 2A (CMT2A) caused by MFN2 mutations and dominant optic atrophy (DOA) caused by 0PA1 mutations; disorders of coenzyme Q10 (CoQlO) biosynthesis manifesting as primary CoQlO deficiency syndromes; and complex-specific deficiencies affecting isolated complexes I, II, III, IV, or V of the respiratory chain. Other related conditions include Barth syndrome resulting from cardiolipin deficiency, Friedreich's ataxia involving frataxin deficiency affecting mitochondrial iron metabolism, Sengers syndrome, and various forms of 3-methylglutaconic aciduria syndromes.

[0074] Mitochondrial DNA Depletion Syndrome

[0075] At present, there are no effective drug treatments for mitochondrial DNA depletion disorders (MDSS). MDDS refers to autosomal recessive disorders and autosomal dominant disorders having a broad genetic and clinical spectrum, and the disorders are characterized by a severe reduction in mtDNA content in affected tissues and organs. FIG. 1 shows a classification of primary mitochondrial disorders into the following categories: mtDNA mutation and / or deletion syndromes, mtDNA depletion syndromes, and POLy mutations.

[0076] MDDS is associated with defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial deoxyribonucleoside triphosphate (dNTP) synthesis or mtDNA replication. Mutations in nuclear-encoded proteins lead to severe disease due to lack of mtDNA. For example, TK2 (thymidine kinase 2), SUCLA2 (adenosine diphosphate (ADP)-forming succinyl CoA ligase beta subunit), SUCLG1 (guanosine diphosphate (GDP)-forming succinyl CoA ligase alpha subunit), RRM2B (ribonucleotide reductase M2 B subunit), DGUOK (deoxyguanosine kinase), and TYMP (thymidine phosphorylase) encode proteins that maintain the mitochondrial dNTP pool; therefore, mutations in any of these genes result in depleting the mitochondria from DNA building blocks and, subsequently, mtDNA depletion. POLy (DNA polymerase gamma) and C10orf2 (Twinkle) are essential for mtDNA replication; therefore, mutations in these genes result in insufficient mtDNA synthesis to keep up with mtDNA turnover and segregation to daughter cells during cell divisions resulting in reduction of mtDNA content.

[0077] In some embodiments, the MDDS or PMD is Alpers-Huttenlocher syndrome (AHS) and the symptom is selected from the group consisting of focal motor seizures,-20- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOgeneralized status epilepticus, refractory convulsive status epilepticus, developmental delay, neurodevelopmental regression, renal dysfunction, hypotonia, epilepsia partialis continua, and any combination thereof.

[0078] In some embodiments, the MDDS or PMD is progressive external ophthalmoplegia (PEO) and the symptom is selected from the group consisting of encephalomyopathy, progressive weakness of the extraocular muscles, bilateral symmetrical ptosis, sensorineural hearing loss, facial myopathy, cataracts and any combination thereof.

[0079] In some embodiments, the MDDS or PMD is mitochondrial neurogastrointestinal encephalopathy (MNGIE) syndrome and the symptom is selected from the group consisting of persistent diarrhea and cachexia related to gastrointestinal dysmotility, ptosis, proximal myopathy, sensory neuropathy, and any combination thereof.

[0080] In some embodiments, the MDDS or PMD is sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) and the symptom is selected from the group consisting of sensory ataxic neuropathy, dysarthria, ophthalmoparesis, myopathy, seizures, and hearing loss.PMD and MDDS related genes and proteins

[0081] Thymidine kinase 2 (TK2) is associated with UniProt ID 000142, NCBI Gene ID 7084, NCBI RefSeqGene accession NG_012234, and the principal NCBI RefSeq RNA sequence NM_004614.4.

[0082] Twinkle mitochondrial DNA helicase (TWNK; also known as C10orf2) is associated with UniProt ID Q96RR1, NCBI Gene ID 56652, NCBI RefSeqGene accession NG 012215, and the principal NCBI RefSeq RNA sequence NM_001157284.1.

[0083] Thymidine phosphorylase (TYMP) is associated with UniProt ID Pl 9971, NCBI Gene ID 1890, NCBI RefSeqGene accession NG 011860.1 (with an additional RefSeqGene record NG_016235.1), and the principal NCBI RefSeq mRNA sequence NM_001953.5.

[0084] Deoxyguanosine kinase (DGUOK) is associated with UniProt ID QI 6854, NCBI Gene ID 1716, NCBI RefSeqGene accession NG 008044.1, and the principal NCBI RefSeq mRNA sequence NM_080916.3.-21- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0085] Ribonucleotide reductase regulatory subunit M2B (RRM2B) is associated with UniProt ID Q7LG56, NCBI Gene ID 50484, NCBI RefSeqGene accession NG 033054.1, and the principal NCBI RefSeq mRNA sequence NM_015713.5.

[0086] Ribonuclease Hl (RNASEH1) is associated with UniProt ID 060930, NCBI Gene ID 246243, NCBI RefSeqGene accession NG_042143.1, and the principal NCBI RefSeq mRNA sequence NM_002936.6.

[0087] Single-stranded DNA binding protein 1 (SSBP1) is associated with UniProt ID Q04837, NCBI Gene ID 6742, does not currently have an NCBI RefSeqGene (NG_) accession, and is represented by the principal NCBI RefSeq mRNA sequence NM_003143.3.

[0088] Mitochondrial genome maintenance exonuclease 1 (MGME1) is associated with UniProt ID Q9H3S7, NCBI Gene ID 79801, NCBI RefSeqGene accession NG 032867.1, and the principal NCBI RefSeq mRNA sequence NM_052998.4.

[0089] DNA replication helicase / nuclease 2 (DNA2) is associated with UniProt ID Q9HAV5, NCBI Gene ID 176319, NCBI RefSeqGene accession NG 033007.1, and the principal NCBI RefSeq mRNA sequence NM_001080449.2.

[0090] Adenine nucleotide translocator 1 (ANTI; SLC25A4) is associated with UniProt ID P12235, NCBI Gene ID 291, NCBI RefSeqGene accession NG_013001.1, and the principal NCBI RefSeq mRNA sequence NM_001151.4.

[0091] Succinate-CoA ligase GDP -forming subunit alpha (SUCLG1) is associated with UniProt ID P53597, NCBI Gene ID 8802, NCBI RefSeqGene accession NG 016755.1, and the principal NCBI RefSeq mRNA sequence NM_003849.4.

[0092] Succinate-CoA ligase ADP -forming subunit beta (SUCLA2) is associated with UniProt ID Q9P2R7, NCBI Gene ID 8803, NCBI RefSeqGene accession NG 008241.2, and the principal NCBI RefSeq mRNA sequence NM_003850.2.

[0093] MPV17 mitochondrial inner membrane protein (MPV17) is associated with UniProt ID P39210, NCBI Gene ID 4358, NCBI RefSeqGene accession NG 008075.2, and the principal NCBI RefSeq mRNA sequence NM_002437.5.-22- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0094] OPA1 (OPA1 mitochondrial dynamin like GTPase) is associated with UniProt ID 060313, NCBI Gene ID 4976, and principal RefSeq RNA transcripts including NM_015560.2 (among other RefSeq RNA variants); the genomic locus for the human OPA1 gene is represented by the RefSeqGene accession NG_011605.1,

[0095] FBXL4 (F-box and leucine rich repeat protein 4) is associated with UniProt ID Q9UKA2, NCBI Gene ID 26235, and the canonical RefSeq RNA transcript NM_001278716.2; the RefSeqGene accession NG_033903.2.

[0096] AGK (acylglycerol kinase) is associated with UniProt ID Q53H12, NCBI Gene ID 55750, and the principal RefSeq RNA transcript NM_018238.4; the genomic locus for human AGK in the RefSeqGene database is represented by accession NG 032079.1.

[0097] Mitochondrially encoded genes are defined on the mitochondrial reference genome (NC_012920.1) and lack UniProt and NG_ identifiers.

[0098] Mitochondrially encoded ATP synthase membrane subunit 6 (MT-ATP6) is associated with NCBI Gene ID 4508 and is encoded on the mitochondrial reference genome NC_012920.1.

[0099] Mitochondrially encoded tRNA leucine 1 (MT-TL1) is associated with NCBI Gene ID 4569 and is encoded on the mitochondrial reference genome NC 012920.1.

[0100] Mitochondrially encoded tRNA histidine (MT-TH) is associated with NCBI Gene ID 4570 and is encoded on the mitochondrial reference genome NC_012920.1.

[0101] Mitochondrially encoded tRNA serine 1 (MT-TS1) is associated with NCBI Gene ID 4571 and is encoded on the mitochondrial reference genome NC_012920.1.

[0102] Mutations in TK2 (thymidine kinase 2) that are associated with mitochondrial DNA depletion syndrome (MDDS) include, but are not limited to, missense mutations such as p. Argl30Trp (c.388C> T), start-loss mutations such as p. MetlVal and p. MetlThr, as well as nonsense, frameshift, and splice-site mutations that result in reduced or absent TK2 enzymatic activity and impaired mitochondrial deoxynucleotide salvage.-23- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0103] Mutations in DGUOK (deoxyguanosine kinase) that are associated with MDDS include, but are not limited to, start-loss mutations such as pMetlThr (c.2T> C), frameshift mutations such as c.204delA, nonsense mutations including p. Gln79Ter and p. Argl42Ter, and other loss-of-function variants that disrupt mitochondrial purine deoxynucleotide phosphorylation and lead to mitochondrial DNA depletion.

[0104] Mutations in SUCLA2 (succinate-CoA ligase ADP-forming subunit beta) that are associated with MDDS include, but are not limited to, missense mutations such as p. Arg284Cys (c.850C> T) and p. Glyl 18Arg, as well as compound heterozygous combinations of missense and truncating mutations that impair succinyl-CoA ligase activity and result in mitochondrial DNA depletion.

[0105] Mutations in SUCLG1 (succinate-CoA ligase GDP-forming subunit alpha) that are associated with MDDS include, but are not limited to, splice-site mutations such as c.826-1G> A, nonsense mutations such as p. Arg407Ter, and other truncating variants that cause severe early-onset mitochondrial DNA depletion. In some embodiments, these SUCLG1 mutations affect the muscle, brain, and liver.

[0106] Mutations in MP VI 7 (MP VI 7 mitochondrial inner membrane protein) that are associated with MDDS include, but are not limited to, missense mutations such as p. Arg50Gln (c,149G> A) and p. Pro98Leu, as well as frameshift and nonsense mutations that disrupt mitochondrial inner membrane homeostasis and lead to mitochondrial DNA depletion.

[0107] Mutations in RRM2B (ribonucleotide reductase regulatory subunit M2B) that are associated with MDDS include, but are not limited to, missense mutations such as p. Argl lOHis (c.329G> A) and p. Argl21His (c.362G> A), as well as truncating mutations that impair deoxynucleotide triphosphate pool maintenance required for mitochondrial DNA replication.

[0108] Mutations in MGME1 (mitochondrial genome maintenance exonuclease 1) that are associated with MDDS include, but are not limited to, nonsense mutations such as p. Trpl52Ter (c.456G> A), frameshift mutations, and other loss-of-function variants that-24- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOdisrupt mitochondrial DNA processing and result in mitochondrial DNA depletion, often in combination with multiple mitochondrial DNA deletions.

[0109] Mutations in TWNK (twinkle mitochondrial DNA helicase; also known as C10orf2) that are associated with primary mitochondrial disease include, but are not limited to, missense mutations such as p. Tyr508Cys (c,1523A> G), as well as other missense, nonsense, frameshift, and splice-site mutations that impair mitochondrial DNA replication and are associated with mitochondrial DNA maintenance disorders, including progressive external ophthalmoplegia and related phenotypes.

[0110] Mutations in TYMP (thymidine phosphorylase) that are associated with primary mitochondrial disease include, but are not limited to, missense mutations such as p. Glu289Ala (c.866A> C), p. Arg44Pro (c,131G> C), and p. Leu423Arg (c,1268T> G), as well as other loss-of-function variants that result in thymidine phosphorylase deficiency. In some embodiments, these TYMP mutations cause mitochondrial neurogastrointestinal encephalomyopathy through toxic nucleoside accumulation and secondary mitochondrial DNA instability.

[0111] Mutations in RNASEH1 (ribonuclease Hl) that are associated with primary mitochondrial disease include, but are not limited to, missense mutations such as p. Vall42Ile (c.424G> A), nonsense mutations such as p. Argl57Ter (c.469OT), and other pathogenic variants that impair mitochondrial RNA primer removal during mitochondrial DNA replication. In some embodiments, these RNASEH1 mutations are associated with autosomal recessive mitochondrial DNA maintenance disorders characterized by multiple mitochondrial DNA deletions.

[0112] Mutations in SSBP1 (single-stranded DNA binding protein 1) that are associated with primary mitochondrial disease include, but are not limited to, missense mutations such as p. Arg38Gln (c.l 13G> A), as well as other variants that impair mitochondrial single-stranded DNA stabilization and replication, resulting in mitochondrial DNA maintenance defects. In some embodiments, these SSBP1 mutations are associated with clinical phenotypes including optic atrophy and multisystem mitochondrial disease.-25- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0113] Mutations in DNA2 (DNA replication helicase / nuclease 2) that are associated with primary mitochondrial disease include, but are not limited to, missense mutations such as p. Ser640Leu (C.1919OT), as well as other pathogenic variants that disrupt mitochondrial DNA repair and processing. In some embodiments, these DNA2 mutations are associated to mitochondrial DNA deletion syndromes and progressive mitochondrial myopathy.

[0114] Mutations in SLC25A4 (adenine nucleotide translocator 1; ANTI) that are associated with primary mitochondrial disease include, but are not limited to, missense mutations such as p. Arg80His (c.239G> A), as well as other dominant or recessive variants that impair mitochondrial ADP / ATP exchange. In some embodiments, these SLC25A4 mutations are associated with mitochondrial DNA maintenance disorders, including mitochondrial DNA depletion or deletion phenotypes.

[0115] Mutations in MT-ATP6 (mitochondrially encoded ATP synthase membrane subunit 6) that are associated with primary mitochondrial disease include, but are not limited to, mitochondrial DNA variants m.8993T> G and m.8993T> C, which impair ATP synthase function. In some embodiments, these MT-ATP6 mutations are associated are associated with the neuropathy, ataxia, and retinitis pigmentosa (NARP) spectrum and Leigh syndrome.10116] Mutations in MT-TL1 (mitochondrially encoded tRNA leucine 1) that are associated with primary mitochondrial disease include, but are not limited to, the mitochondrial DNA variant m.3243 A> G, as well as other pathogenic variants that disrupt mitochondrial protein translation. In some embodiments, these MT-TL1 mutations are associated with the MELAS spectrum and related mitochondrial disorders.

[0117] Mutations in MT-TH (mitochondrially encoded tRNA histidine) that are associated with primary mitochondrial disease include, but are not limited to, the mitochondrial DNA variant m,12192G> A and other pathogenic variants that impair mitochondrial translation. In some embodiments, these MT-TH mutations are associated with mitochondrial cardiomyopathy and multisystem mitochondrial disease.

[0118] Mutations in MT-TS1 (mitochondrially encoded tRNA serine 1) that are associated with primary mitochondrial disease include, but are not limited to, mitochondrial DNA variants m.7445A> G, m.7512T> C, and insertion variants such as m.7472insC, which impair -26- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOmitochondrial tRNA function. In some embodiments, these MT-TS1 mutations are associated with a spectrum of mitochondrial disease phenotypes, including hearing loss and myopathy.

[0119] Mutations in OPA1 that are associated with primary mitochondrial disease (PMD) include, but are not limited to, pathogenic splice-region and missense variants reported in autosomal dominant optic atrophy and syndromic “DOA-plus” phenotypes, including variants such as c.870+5G> A and C.2713OT, as well as other missense, nonsense, frameshift, and splice-site mutations that disrupt mitochondrial inner membrane fusion, cristae organization, and mitochondrial genome integrity. In certain subjects, OPA1 mutatns have also been associated with more severe early-onset encephalomyopathic presentations with evidence of impaired mtDNA maintenance (including reduced mtDNA levels in patient-derived fibroblasts).

[0120] Mutations in FBXL4 that are associated with PMD and / or mitochondrial DNA depletion syndrome (MDDS / MTDPS13) include, but are not limited to, biallelic pathogenic variants that reduce or abolish FBXL4 function and are associated with infantile-onset encephalomyopathy, persistent lactic acidosis, and reduced mtDNA copy number, epresentative reported disease-associated variants include missense changes such as C.1303OT, as well as additional missense, nonsense, frameshift, splice-site, and other loss-of-function variants (including deletions) described in affected individuals.

[0121] Mutations in AGK that are associated with PMD, including Sengers syndrome and AGK-related mitochondrial disease, include, but are not limited to, biallelic predicted loss-of-function variants such as frameshift deletions c.523_524delAT (p. Ilel75Tyrfs*2) and c,1035dup (p. Ile346Tyrfs*39), nonsense variants C.409OT (p. Argl37*) and C.871OT (p. Gln291*), and splice-site variants including c.424-lG> A and c.877+3G> T, as well as other missense, nonsense, frameshift, splice, and gross deletion mutations reported across affected families.

[0122] POLG activators

[0123] The present disclosure describes small molecules that act as activators of mtDNA synthesis. The compounds increase the amount of mtDNA in the treatment of mitochondrial-27- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOdepletion disorders in patients where there is no mutation in the POLy gene. These compounds are referred to herein as “POLg activators.”

[0124] Experimental Data: Data described herein demonstrates the effectiveness of multiple compounds (e.g., having structures as defined in formula (I), (II), (III), (IV), and (V), and Tables 1-5) to increase mtDNA copy number in multiple POLy mutant patients, the positive results are not limited to a specific POLy mutation.

[0125] FIG. 2 shows a graph demonstrating that proliferating WT cells do not show a different rate of mtDNA recovery when treated with DMSO compared to treatment with 1 pM of a POLg activator described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea). In proliferating WT, non-diseased cells, POLG activity is not rate-limiting. FIG. 3A-D demonstrate that treatment with POLg activators described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea (Cl), (S)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(l-methyl-lH-pyrazol-3-yl)thiazol-4-yl)urea (C2), l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol -4-yl)urea (C3), and (S)-l-(8-chlorochroman-4-yl)-3-(2-(l-cyclopropyl-lH-imidazol-4-yl)thiazol-4-yl)urea (C4) accelerated mtDNA recovery relative to a control for quiescent mutant MPV17, RRM2B, and DGOUK patient fibroblasts. FIGs. 4A & B show that the POLg activators described herein (e.g., l-[(4S)-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)urea) increase mtDNA copy number in the presence of TWINKLE mutations that lead to MDDS. FIG. 5 shows that POLg activators described herein (e.g., l-[(4S)-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)urea) increase mtDNA copy number in the presence of TK2 mutations that cause MDDS. FIGs. 6A and B show that the POLg activators described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea) elicit positive pharmacology in a DGUOK-KO mice model. FIG. 7A and 7B show results of two independent experiments where POLg activator-treated TK2 KO mice lived longer and had more mtDNA copy number than vehicle-treated mice.II. Methods

[0126] Provided herein are methods of treating a disease or disorder using a POLG activator in a subject in need thereof. In some embodiments, the disease or disorder is a Primary Mitochondrial Disorder (PMD). In another aspect, provided herein are methods of treating-28- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOMDDS in a subject in need thereof. In another aspect, provided herein are methods of treating a PMD or MDDS. The method comprises optionally identifying a subject diagnosed with, or at risk of developing, a MDDS, followed by administering a therapeutically effective amount of a compound of formula I, II, III, IV, or V, or a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, where the subject does not have a mutation in the DNA polymerase y gene (POLG).

[0127] In one aspect, the compound is a compound is disclosed in (1) PCT Application No. PCT / US24 / 37620, filed July 11, 2024, titled Modulators of Mitochondrial DNA Replication, (2) PCT Application No. PCT / US24 / 38000, filed July 14, 2024, titled Modulators of Mitochondrial DNA Replication, (3) PCTApplication No. PCT / US2025 / 039097, filed July 24, 2025, titled Modulators of Mitochondrial DNA Replication, (4) PCT Application No. PCT / US25 / 25401, filed April 18, 2025, titled Modulators of Mitochondrial DNA Replication, and / or (5) PCT Application No. PCT / US2025 / 046383, filed September 15, 2025, titled Modulators of Mitochondrial DNA Replication. All of the foregoing patent applications are incorporated herein by reference.

[0128] In one aspect, provided herein is a method of treating PMD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by formula (I):or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, C1-C3 alkyl, Cl, F, and CN;R2is H or C1-C3 alkyl substituted with OH or OCH3;R3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH;R4is each independently H or C1-C4 alkyl;-29- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOZ is selected from the group consisting of Ci-Ce alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-heterocyclyl, and aryl-heteroaryl, wherein: (1) Ci-Ce alkyl is optionally substituted with one or more groups each independently selected from the group consisting of phenyl, OH, C(O)OH, C(O)NR6R7, NR5R5, NR5-C(O)CH3, SO2R5, aryl, heteroaryl, and aryl-heteroaryl, (2) cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, C(O)NR5R5, NR5R5, and NR5-C(0)CH3, (3) heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of keto, C3-C6 cycloalkyl, C(0)CH, C(O)O-Ci-C3 alkyl, C(O)NR5R5, SO2-C1-C3 alkyl, and C1-C4 alkyl that is optionally substituted with OH, (4) aryl is optionally substituted with one or more groups each independently selected from the group consisting of: C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of F, OH, and NR5R5, C3-C6 cycloalkyl that is substituted with NR5R5, halogen, CN, OR5, C(O)OH, C(O)NR6R7, R6R7, SO2R5, SO2NR5R5, and 4- or 6-membered heterocyclic ring that is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C1-C4 alkyl, andNR5R5, (5) heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)NR5R5, OR5, NR5R5, OXO, SO2R5, and C1-C4 alkyl optionally substituted with a group selected from the group consisting of NR5R5, OR5, and C(O)NR5R5, (6) aryl-heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of chloro, fluoro, and C1-C4 alkyl that is optionally substituted with one or more groups each independently selected from the group consisting of OH, O-C1-C3 alkyl, chloro, and fluoro; and (7) aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OH;R5is each independently H or C1-C4 alkyl;R6is H or Ci-Ce alkyl optionally substituted with one or more groups each independently selected from the group consisting of halogen, CN, and NR5R5;R7is H or C1-C5 alkyl optionally substituted with one or more groups each independently selected from the group consisting of hydroxyl, NR5R5, heteroaryl, and heterocyclyl optionally substituted with C1-C5 alkyl or CN, or-30- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOR7is C1-C5 alkyl substituted with C3-C6 cycloalkyl optionally substituted with a group selected from the group consisting of O-C1-C5 alkyl, CN, NR5R5, and one or more fluoro, orR7is C3-C5 cycloalkyl optionally substituted with Ci alkyl optionally substituted with OH, orif R6and R7are attached to the same nitrogen atom, then R6and R7together with their connecting nitrogen form a 3- to 6-membered heterocyclic ring optionally containing another heteroatom that is O or N and optionally substituted with C1-C5 alkyl;n is 1-4;p is 1-2; owith the proviso that a compound is not selected from the group consisting of:l-(l,5-dimethyl-l / 7-pyrazol-3-yl)-3-(8-methylclhr comjan-4-yl)urea,l-(8-methylchroman-4-yl)-3-(l-(l-methylpiperidin-4-yl)-U / -pyrazol-3-yl)urea,T Zl-(l-(2-(dimethylamino)ethyl)-l / 7-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea,ZE Zl-(l-( ec-butyl)-5 -methyl- l / 7-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea, andl-(8-fluorochroman-4-yl)-3-(l-(pyridin-4-ylmethyl)-U / -pyrazol-3-yl)urea.

[0129] In an embodiment, a compound of formula 1 is identified in Table 1:0Table IIIIChemical Name Structure z (5)-l-(8-chlorochroman-4-yl)-3-(l-(4- cy anophenyl)- 1 / 7-py razol -3 -yl)urea(5)-l-(8-chlorochroman-4-yl)-3-(l-(2- O-- methoxypyridin-4-yl)-U / -pyrazol-3- cz A. A. A A >-Ayl)urea Z --Y N' w -NVNz AH(5)- 1 -(8-chlorochroman-4-yl)-3 -(1 -(3 - N cyanophenyl)- 1 / 7-py razol -3 -yl)urearT 1 1 X / -Z i| J H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- O 'A 0Z-N ' (dimethylamino)ethyl)-l / / -pyrazol-3- n.1 J HN"-'yl)urea N' " N " N(5)-4-(3-(3-(8-chlorochroman-4- O'*' 0 \ yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V,7V- CL. J. J. JI £ H— / " A dimethylbenzamide Y 'Y V' 'TT' ’"hr Y Aij H b (5)-4-(3-(3-(8-chlorochroman-4- 0 / A NH2yl)ureido)- UZ-pyrazol- 1 -yl)benzamide I 1 zUy j H H -■ (5)- 1 -( 1 -(4-(2-aminopropan-2- yl)phenyl)- lJ7-pyrazol-3 -y l)-3 -(8-chloro- 1 JAAA_Z.H25 -fluorochroman-4-yl)urea N Y-'S' v / v Hx1 -( 1 -ethyl- 1 / / -py razol -3 -y 1 )- 3 -(8 - fluorochroman-4-yl)urea C: C'" A o£T Wy j K Hl-((5)-8-chlorochroman-4-yl)-3-(l-(4- H (4,4-difluoropyrrolidin-2-yl)phenyl)-lJ7- LCl..... As. ''N N-A 1N--(pyrazol-3-yl)urea T"N' X4-r Fl-((5)-8-chlorochroman-4-yl)-3-(l-(4- p'x’A c(4,4-difluoropyrrolidin-2-yl)phenyl)-lJ7- pyrazol-3-yl)urea 4 A N:JHF1 ■[ 1 -[4-( 1 -aminocyclopropyl) phenyl] cA'A <:pyrazol-3-yl]-3-[(45)-8-chlorochroman- ci....4 A,i 1 M 4-yl]urea 'N' ’N A AA 1 J H H “■ l-[(45)-8-chlorochroman-4-yl]-3-[l-[4- (A " A O p [2-(dimethylamino)- 1, 1 -difluoro- cu A AAA'Hethyl ]pheny 1 ] py razol -3 -y 1 ]ureall JHAIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- 0 \ [(l-(dimethylamino)ethyl] phenyl] Ck X 1 JI i- N-Z -X'— pyrazol-3-yl]ureaH H '■ l-[(45)-8-chlorochroman-4-yl]-3-[l-[4- cy "■-! o \ [(l-(dimethylamino)ethyl] phenyl] Ck. X J. 11 J.pyrazol-3-yl]urea (i 'Y Z 'N' A'-';HH1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 -0■' <::[1 -methyl- 1 -(methylamino) ethyl]phenyl]. J.. KN;’Ypyrazol-3-yl]urea.... O-NH l-[l-[4-(azeti din-3 -yl) phenyl] pyrazol-3- O'" A Q A y 1 ] -3 - [(45)- 8 -chi orochroman-4-y 1 ]urear,< i As A,- A — \ NH A.,, - ' NNI JH2-(3 -(3 -(8-fluorochroman-4-yl)ureido)- F1 / / -pyrazol -1 -yl )-A( A -di methyl acetamideH A HA.<I T N 'o1 ■[ 1 -[4-(3 -aminooxetan-3 -yl)phenyl] O’ A O YA \JM. pyrazol-3-yl]-3-[(45)-8-chlorochroman- I j I Si YN-- 4 A-...■ '' ' N ' ’’N Y # '7'Y 4-yl]urea ( J H H;-..k l-[(45)-8-chlorochroman-4-yl]-3-[l-[4-Q" " ■)[l-methylpyrrolidin-2-yl] phenyl] 9 ZY,Cks.xy.. A: J, A N-—< 0 pyrazol-3-yl]urea N '"""' N ''N 'w / “X J H Hl-[(45)-8-chlorochroman-4-yl]-3-[l-[4- [l-methylpyrrolidin-2-yl] phenyl]? rw A pyrazol-3-yl]urea N ’''VN ' \^ / " X J H IIl-[(45)-8-chlorochroman-4-yl]-3-[l-[4- [1 -methyl- 1 -(methylamino) ethyl] ck X l lphenyl] pyrazol-3-yl]urea y j H H ■ * "IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- o( 1 -methyl azeti din-3 -y l)pheny 1 ] py razol -3 - Ck... L I A N- " N zyl]urea AO H1 ■[ 1 -[4-(l -amino- 1 -methyl-ethyl)-3 - fluoro-phenyl]pyrazol-3-yl]-3-[(45)-8- Ck. X A. A AN’A, \.-...z chlorochroman-4-yl]urea Y kr 'W '" N ' ‘H Ak J H H A ' l-[(45)-8-chlorochroman-4-yl]-3-[l-[4- 0[2-(dimethylamino)acetyl] Ck.sA J. J,k N \,Gpheny 1 ] py razol -3 -y 1 ]urea ■ -y tr A' " AzJ H H - / \1 -[ 1 -[3 -fluoro-4-(2- )O \\ / ~ / \ / \ hydroxyethylamino)phenyl]pyrazol-3- oyl]-3-[(45)-8-chlorochroman-4-yl]urea ■ X J-- ZZN- X N' 'N WJHH IZ1 -[ 1 - [6-( 1 -amino- 1 -methyl-ethyl)-3 - py ri dy 1 ] py razol -3 -y 1 ] -3 - [(45)- 8 - Ck ■-k. s-'1-. A t-.. N — -Z V z chlorochroman-4-yl]urea y w' w' Af 91 H H / \ ■ 1 - [ 1 - [4- [ 1 -amino-2,2,2-trifluoro- ethy 1 ]pheny 1 ] py razol -3 -y 1 ] -3 - [(45)- 8 - Ckchlorochroman-4-yl]urea A z -n 1 A m1 - [ 1 - [4- [ 1 -amino-2,2,2-trifluoro- O r~, ethy 1 ]pheny 1 ] py razol -3 -y 1 ] -3 - [(45)- 8 - Ck A A / chlorochroman-4-yl]ureaNH2j nNAZ A k F Fl-[(45)-8-chlorochroman-4-yl]-3-[l-[4- H [pyrrolidin-2-yl] phenyl] pyrazol-3- Cz, z-OA W 'l yl]urea - 1 <z- 1 'p J A k \ J Hl-[(45)-8-chlorochroman-4-yl]-3-[l-[4- [pyrrolidin-2-yl] phenyl] pyrazol-3- Ck Y 1 ii r W A / S ■ A'- / . | A-'W \ / “'V yl]urea k jsj N 1* \] J H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- 0 X[2-(dimethylamino)ethyl] 0zXCK X- P k Hpheny 1 ]py razol -3 -y 1 ]urea X" N """ N V. / H H1 ■[ 1 -[4-(l -amino- 1 -methyl- ethyl)phenyl]pyrazol-3-yl]-3-[chroman- 1 * 14-yl]urea j 4. ' JX 'NH' H1 ■[ 1 -[4-( 1 -amino- 1 -methyl- ethyl)phenyl]pyrazol-3-yl]-3-[chroman- 11ZXAX / I — Xh-A 4-yl]urea ■'N ’N..<1 ■1Hl-[(45)-8-chlorochroman-4-yl]-3-(l- 9X 0phenylpyrazol-3-yl)ureaw,, N JI j A.A J H ■» H-' -'hf VX. z l-[(45)-8-fluorochroman-4-yl]-3-(l- phenylpyrazol -3 -yl)urea R X fl oA 1.. N-A7A 1 N '* w1 ■[ 1 -[4-( 1 -amino- 1 -methylethyl)phenyl]pyrazol-3-yl]-3-[(45)-8- ii L > X^X / chlorochroman-4-yl]urea ''M'z S'M'X'Z f' H Hl-[(45)-8-methylchroman-4-yl]-3-(l- OX 0 r^-\ _ phenylpyrazol -3 -yl)urea A A. X, A. A.. N~Z %X 4 i r « w1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3 - C)Xfluorophenyl) pyrazol-3-yl] urea Ck A J A J N..-. A AN N" Af / H H1 -[ 1 -(3 -fluorophenyl) pyrazol-3 -y 1 ] -3 - 0 / [(45)-8-methylchroman-4-yl]urea? XX J J > A L bXX.A A r H w1 -[ 1 - [4-( 1 -amino- 1 -methylethyl) o-Xphenyl]pyrazol-3-yl]-3-[(45)-8- Fx A Afluorochroman-4-yl]urea " Ar-"' J' j L ^XX >' N " A \\ zX: lx 4 H •" IxIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(6- methoxy-3-pyridyl)pyrazol-3-yl]urea'L ' " N W ~ [1 J H Hl-[(45)-8-chlorochroman-4-yl]-3-(l- O'Y 0tetrahydropyran-4-ylpyrazol-3-yl)urea C!.. X JN " M N V, / H 4V3-[3-[[(45)-8-chlorochroman-4- y 1 ] carb amoy 1 amino] py razol - 1 - r-NiL yl]benzamider Y-XXCl.. X x''N" ■N ' Y Y / IJ H H1 ■[ 1 -[4-[2-(dimethylamino)0ethoxy ]pheny 1 ] py razol -3 -y 1 ] -3 - [(45)- 8 - / J—CL J, Jchlorochroman-4-yl]urea f Y H 1 r^N'NX.,. Oo / X>l-[(45)-8-chlorochroman-4-yl]-3-[l-[4- Q-Y 0F[1, l-difluoro-2- (methylamino)ethyl] ClxX. J H NYphenyl] pyrazol-3-yl]urea '" IT N " " N A Y \H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 -Z--N" [2-(methylamino)ethoxy] 0 - x pheny 1 ]py razol -3 -y 1 ]urea oYClx^X 1 OXYH Kl-(8-chloro-2-(methoxymethyl)chroman- 4-yl)-3-(l-phenyl-U7-pyrazol-3-yl)ureaoX OCL il i- N- Y \\7i Y N N N L_ / XjHHIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structurel-(8-chloro-2-(methoxymethyl)chroman- 4-yl)-3-(l-phenyl-U7-pyrazol-3-yl)urea,0r0’ 0CK X ii ¥ N:■ ¥ N N NI JH Hl-[8-chloro-2-(hydroxymethyl)chroman-. OH4-yl] -3 -( 1 -phenylpyrazol -3 -yl)urea9^1 ° ¥¥, — >Ci\ A A X N-AA 4 N N N' V / N J H Hl-[8-chloro-2-(hydroxymethyl)chroman- OH4-yl]-3-(l-phenylpyrazol-3-yl)ureaO'A OclxAs. A A X \\ ¥ ¥ N ¥ N V / ¥^4 H H1 -[(45)-8-fluorochroman-4-yl]-3 -[ 1 -(3 - X'X O -?fluorophenyl) pyrazol-3-yl]ureail A LY Y N‘ N- 'N' V '- H Hl-[8-chloro-2-(hydroxymethyl)chroman- 4-yl]-3-(l-phenylpyrazol-3-yl)urea rH0 *¥ O r--“\A A- N-XX ¥| ¥ N 'N N V. / I! J H Hl-[8-chloro-2-(hydroxymethyl)chroman-. OH4-yl] -3 -( 1 -phenylpyrazol -3 -yl)ureack A A A A- Y N N N X / y J H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure 2-(3 -amino- 1 / 7-py razol -1 -yl)-7V, N- 0 dimethylacetamide 9 4 0J.. J.. H 9.... N-A \ X' "N' 'N"' 'NL 9 H Hl-[(45)-8-chlorochroman-4-yl]-3-[l-[4- [(dimethylamino)methyl]pheny 1 ]py razol -3 -y 1 ]urea ■■ A - " N A. YJ X H Hl-[(45)-8-chlorochroman-4-yl]-3-[l-(2- 9‘X 0methoxypyrimidin-5-yl) pyrazol-3- Ck A J Ji.,. A..N'~ 9 Xr / yl]urea Y X N N 0... A1 J H Hri5-[3-[[(45)-8-chlorochroman-4- X""'9 9 \ yl]carbamoylamino]pyrazol- 1 -y 1 ] -N- Cl... X X.. A. X JX ”9NHmethyl-pyridine-2-carboxamide lxHH "-■N 9 0 'Z1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3 - Xmethyl sulfonylphenyl) pyrazol -3 -yl]urea n zs^-f '0 0 L \ CK X..-A,HX. XF 4-[3-[[(45)-8-chlorochroman-4-yl]n'"'"-: O AA HN-- carbamoyl amino]pyrazol- 1 -yl]-2-fluoro- i h.9.NX 9—47V-m ethyl -b enzami deGkX'X / '" A " N " N o x H JH Hl-[(45)-8-chlorochroman-4-yl]-3-[l-(2- A A 9 YVmethyl-4-pyridyl)pyrazol-3-yl]ureaT -< " N' N A 9 XJ H H X0 -- 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3,4- dimethoxyphenyl)pyrazol -3-yl]urea ci.. X J J L x- / 9 y y ■■■< w 9T 'N’ V, X° U... J H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4- O'X o X’A pyridyl) pyrazol-3-yl]urea n > 1 JL >y J: H IIIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure1 -[(4S)-8-chlorochroman-4-yl]-3 -[ 1 -(4- O""x■I 0pyridyl) pyrazol-3-yl]urea CR A 1. JI I. N-X 1N' N- 'A V AT H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(3 - F fluoro-4-methoxyphenyl)- 1 / 7-py razol -3 - O'""'"- 1? AA / yl)urea CL. A- •- H H I Jl-[(45)-8-chlorochroman-4-yl]-3-(l- O,z" A 9tetrahydropyran-4-ylpyrazol-3-yl)urea CL. R. J A.,N"XNH 'N' 'N v,.y H JH1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[ 1 - 9 f L A X / --OH (2-hydroxyethyl)-4-piperidyl]pyrazol-3- hr N \ / yl]urea H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3 - oxxpyridyl) pyrazol-3-yl]urea CL A ' I, 1 JZ >... / ■ "N\-N' -N" ‘CM A / I HN.- T H< A1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3,4- 0 h 0 ■ difluorophenyl) pyrazol-3-yl]ureaCR A J, A kN-A A( J H HN1 ■[ 1 -[4-(l -amino- 1 -methylethyl)-2- O'"“x0 fAAXfluoro-phenyl]pyrazol-3-yl]-3-[(45)-8- ci v 7... - 7 A A N \ / chlorochroman-4-yl]urea 1 " T 'N IT 'NH Hf / l-[(45)-8-chlorochroman-4-yl]-3-[l-(2-. A° methyl sulfonylphenyl) pyrazol -3 -yl]urea o vCR A 1. A W 1A A H' A 'N' v 77 H H “• l-[(45)-5-fluorochroman-4-yl]-3-(l- (A Y 0phenylpyrazol -3 -yl)urea 1 J. j( j ••X, C ><(X- RR -NX A Ayy jH HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure1 ■[ 1 -[5-(l -amino- 1 -methyl-ethyl)-2- opy ri dy 1 ] py razol -3 -y 1 ] -3 - [(45)- 8 -. A O-4NH. chlorochroman-4-yl]urea N N N-A \XH Hl-[(45)-8-chlorochroman-4-yl]-3-[l-(2- c Apyridyl) pyrazol-3-yl] 11a1. N \\ yA' N N ' NH Hl-[(45)-7-fluorochroman-4-yl]-3-(l- 9 7 ophenylpyrazol -3 -yl)urea A J. M 9 n-A %f A ' IAAN' X 9, J.::J H H ■- F '' -O- (5)-3 -(3 -(3 -(8-chlorochroman-4- 0 yl )ureido)-l / / -pyrazol- 1 -yl)-7V- / -NH methylbenzamide a ’A Q Ak. z^-’i< A N hr ’'A A #( J H H(5)-4-(3-(3-(8-chlorochroman-4- 0yl )ureido)-l / / -pyrazol- 1 -yl)-7V- li"■AA' AAA methylbenzamide ' N'"H " “ 0 (5)-3 -(3 -(3 -(8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)-A, N- dimethylbenzamide o-'AN"" N -"‘A' V / H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4,4- CANdifluorocyclohexyl) pyrazol-3-yl]urea to. A. J- 'N ' I 'NZX.N~< kFH H(5)-2-(3-(3-(8-chlorochroman-4- yl )ureido)-l / / -pyrazol- 1 -yl)-A, N- ACdimethylbenzamide O'" A9co...N "'L'" " N " N A ■■■ / H H(5)-l-(8-chlorochroman-4-yl)-3-(l-(4- o,-^x 9 / (trifluoromethoxy)phenyl)-l / / -pyrazol-3- Ci J-. J. 11 0 N \\. Ad' yl)urea K Y A AA~'°l-l-40- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOXTable 1 z 0 Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4- 0.. A. ' methyl sulfonylphenyl) pyrazol -3 -yl]urea ci....4. J..8 fX. p -zr— 0 T? 'V 'N A r V X Ak Jri- 6,z(iz. 'l-[(45)-8-chlorochroman-4-yl]-3-[l-[2- cr'X o x '" OH (hydroxymethyl)-2,3-dihydrobenzofuran- CI.. X, A> J. Vd 4'N ■' 'AM'5 -y 1 ]py razol -3 -y 1 ]urea l.[ J H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[2- (hydroxymethyl)-2,3-dihydrobenzofuran- Cl.. A.. J.,. JlA A"" N5 -y 1 ]py razol -3 -y 1 ]urea 1 H H(5)-4-(3-(3-(8-chlorochroman-4- 0yl)ureido)- 1 / 7-py razol - 1 -yl)-7V- rxCL X X OAA? / methylbenzenesulfonamide AI J I f 'N1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - VC’: H □'"" A, 0., A -... (m ethyl sulfamoyl) phenyl] pyrazol -3- 0 Xyl]urea %4. J. F'A 1.r'X V Zi b z^Z " 0 X ’■ '"1 i J X(5)-4-(3-(3-(8-chlorochroman-4- A'" Xyl)ureido)- 1 / Z-pyrazol- 1 -yl)-7V,3 - C(.. X J. 0 HM oK dimethylbenzamide ' N \-..-z 7 "’o “A O " H 0 ~n (l-[(45)-8-chlorochroman-4-yl]-3-[l-(4- methoxyphenyl)pyrazol -3 -yl]ureac|. JX Pf i NH N? zk’il l-[(45)-8-chlorochroman-4-yl]-3-[l-[4- XX 0(1 -hydroxy- 1 -methyl-ethyl) CK A J. 1 "[-.j..... / Z PH pheny 1 ]py razol -3 -y 1 ]urea c >I J 41 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(2,2- difluoro- 1, 3 -b enzodi oxol -5 -y l)py razol -3 - yl]urea M Ap JIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -( 1 - methyl-4-piperidyl)pyrazol-3-yl]urea CO A x 1 ■ V J. 'N ' Y " NN-x V. / X - - IJ H H4-[3-[[(45)-8-chlorochroman-4- fl.y 1 ] carb amoy 1 amino] py razol - 1 -y 1 ] -3 - f, 0 HO- fluor o-A-m ethyl -b enzami deri; J il X / V, / -i(J--f Y "< TN;tl-[(45)-8-chlorochroman-4-yl]-3-[l-(4- hydroxyphenyl)pyrazol-3-yl]ureaLyj / p / ...H A- y X -p V 7o ■k... X"- 0H X1 -[(45)-chroman-4-yl]-3-[ 1 -(3 - o... / 'px. methylsulfonylphenyl)pyrazol-3-yl]urea 0 > 0 0C Xz X x..r- J. il. A— <: y >TZ1:H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - ' z \ pH (1 -hydroxy- 1 -methyl- O' 'N 0 _ / ' ethy l)pheny 1 ] py razol -3 -y 1 ]urea Ck,. A J J. J.. W Xli Y Y " N - " Ni J 1 A. l-[(45)-8-chlorochroman-4-yl]-3-[l-(5,6- dimethoxy-3 -pyridyl) pyrazol-3-yl]urea1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - F fluoro-4-(methylamino) phenyl]pyrazol- O ” 0 / 3-yl]urea cu„, t ■N'.1 N' 'N w H H1 -[(45)-chroman-4-yl]-3 -[ 1 -[4- (methylsulfamoyl)phenyl]pyrazol-3- j 1 J Vs-NH yl]urea 1 H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[6- O '" \ 0(methylamino)-3-pyridyl] pyrazol-3- Civ V-NH yl]urea X; xy N N N v -;z i| JH r-42- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 1Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- [2,2,2-trifluoro-l -hydroxya,...ethyl ]pheny 1 ] py razol -3 -y 1 ]urea N" A x / H H x-f r l-[(45)-8-chlorochroman-4-yl]-3-[l-[4- [2,2,2-trifluoro-l -hydroxyt'X... JO S■' " N " A X / ethyl ]pheny 1 ] py razol -3 -y 1 ]urea ] H 1-1 x-A r 6-[3-[[(45)-8-chlorochroman-4- o HN— y 1 ] carb amoy 1 amino] py razol - 1 -y 1 ] -N- Cl, X N N Xi methyl-pyridine-3 -carboxamide0l-[(45)-8-chlorochroman-4-yl]-3-[5- Q-, / / Sx methyl- 1 -(3 -methyl sulfonylx-A0pheny l)py razol -3 -y 1 ]urea?z1 ¥ k H-X Xs ' N ' " f ' " M x / 1 J H Hl-[(45)-8-chlorochroman-4-yl]-3-[4- 0, / methyl- 1 -(3 -methyl sulfonyl phenyl) z>xx „ X XS.., U 's o V-x... _ Z " Q pyrazol-3-yl]urea Cl 1 J. ii L N-.. X'r Av- -yr \ / xJHH - - l-(8-cyanochroman-4-yl)-3-(l-phenyl- l / 7-pyrazol-3-yl)urea A X X AN N WU, JH Hl-(8-cyanochroman-4-yl)-3-(l-phenyl- 0 " ' cl / 7-pyrazol-3-yl)urea [ J 1 A N—A A N N 'y~- / X y H H(5)-5-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / Z-pyrazol- 1 -yl) picolinamide Ck A'l iA N N N V,x 'X J H H: N0 (5)- 1 -( 1 -(4-(2-aminopropan-2- O '* O '-‘C"'. Mi— -1 yl)phenyl)-l / 7-pyrazol-3-yl)-3-(8-chloro- 1 i ll; M / Xck A A A, ZN~A AA. 6-fluorochroman-4-yl)urea 'V ■'V N' -N V / \[ H H"fIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 1 CM T ZChemical Name Structure(5)-4-(3-(3-(8-methylchroman-4- yl)ureido)- UZ-pyrazol- 1 -yl) benzamideJ 1 H H 0 °(5)- 1 -( 1 -(2-(dimethylamino)ethyl) -1H- pyrazol-3-yl)-3-(8-methyl chroman-4- QZTyl)ureaZT(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- methylbenzenesulfonamide p Co(5)-4-(3-(3-(8-chlorochroman-4- F yl)ureido)- UZ-pyrazol- 1 -yl)-2- i | 9 / NH2CL 1 1 IZIZ X X. f _ / fluorobenzamideh l > H° H - 0IZ IZ(5)-4-(3 -(3 -(8-fluorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl) benzamide / ° 1J X V\ \(5)-4-(3-(3-(8-chlorochroman-4- / / ( ° yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(2- CL 1 1 II C N— / \ / ? hydroxyethyl)benzamide [1^ 1HH ' ' HN_A-OH 4-(3-(3-((5)-8-chlorochroman-4- 0yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l -Cl\ A J. 1 1 J5hydroxypropan-2-yl)benzamide Xjf " H BN' XX 7 AQH4-(3-(3-((5)-8-chlorochroman-4- oyl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l -ck A J. 1 1 NVX / Z0hydroxypropan-2-yl)benzamide XJ 'XBN' v / X / XQH(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(2- CL i J. ii £7A_ / \ p (dimethylamino)ethyl)benzamide H H A\IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 1Chemical Name Structure(5)-4-(3-(3-(8-chlorochroman-4- fS? ' \ \ / ° yl)ureido)- 1 / Z-pyrazol- 1 -yl)-7V-(2-CI\Z%Z> N^N / ^NZ\=== / A, / — NiH (methylamino)ethyl)benzamide || J] H H HN— y (5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / Z-pyrazol- 1 -yl)-7V- CL ± 1 < \) — / (cyclopropylmethyl)benzamide ||^J H H - 4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / Z-pyrazol- 1 -yl)-7V-(l -? O-ZZ / ° hydroxypropan-2-yl)benzamideCOI'^Y T:Z JZJ H H ~~\ -==} ' H \N-Y / YDH4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / Z-pyrazol- 1 -yl)-7V-(l - 5 AZZ_ / ° hydroxypropan-2-yl)benzamide I J H IZ H - / HN-Y YDH(5)-4-(3-(3-(8-chlorochroman-4- O TZ _ yl)ureido)- 1 / Z-pyrazol- 1 -yl)-7V-(l - Ok 1 1 II f o (hydroxymethyl)cyclopropyl) benzamideH H' ' HN-Z> ^—OH (5)- 1 -(8-chlorochroman-4-yl)-3 -(1 -(5 - (X / (methylsulfonyl)pyridin-3-yl)-l / 7-0r==\ XCj° m pyrazol-3-yl)urea Ok 1 J JJ fjrV'fl(5)-6-(3-(3-(8-chlorochroman-4- ZZ 9 NH2yl)ureido)- 1 / Z-pyrazol- 1 -yl) nicotinamide~ V_ / { || \ H HIN0 (5)-l-(8-chlorochroman-4-yl)-3-(l-(4-0<^° methoxy-3 -(methyl sulfonyl) phenyl)- 1H- pyrazol-3-yl)urea Cl 1 1 JI Z \ r / || 1 H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(3 - fluoro-5-(methylsulfonyl) phenyl)- 1 / 7- pyrazol-3-yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure (5)-5-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / Z-pyrazol- 1 -yl) pyrimidine- 2-carboxamide || J H HN0 (5)-l-(8-chlorochroman-4-yl)-3-(l-(2- 0 (methylsulfonyl)ethyl)-l / 7-pyrazol-3- yl)urea X 1A J V A 6H H(5)-5-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl) pyrazine-2- carb oxami de o(5)- 1 -(8-fluorochroman-4-yl)-3 -( 1 -(4- o0methoxy-3 -(methyl sulfonyl) phenyl)- 1H- pyrazol-3-yl)urea F 1 1 IZ 11 7s* — <([I 1Hh°HIZ(5)- 1 -(8-chlorochroman-4-yl)-3 -(1 - cyclopropyl-l / Z-pyrazol-3-yl) urea a X )- L JH H(5)- 1 -( 1 -( 1 -acetylpiperidin-4-yl)- 1H- pyrazol-3-yl)-3-(8-chloro-chroman-4- yl)urea I ro (5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -( 1 - i sopropylpiperidin-4-yl)- 1 / 7-py razol -3 - yl)urea(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - ethylpiperidin-4-yl)-l / 7-pyrazol-3- yl)urea [ 1H H(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / 7-pyrazol - 1 -yl)-7V,7V- dimethylacetamideCln■xX || X 1 ""*NX>^N'X^NH HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure2-(3-(3-((5)-8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V,7V- O r^\ * V-h / dimethylpropanamide CL JL J., JI / \ h l H H2-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V,7V- dimethylpropanamide1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - 0Omethyl-2-oxopiperidin-4-yl)-lJ7-pyrazol- CAA0AX / — C 3-yl)ureaII 1H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -( 1 - cyclopropylpiperidin-4-yl)-lJ7-pyrazol-3- IZyl)urea || \ H HIZ1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - methylpyrrolidin-3-yl)-lJ7-pyrazol-3- yl)ureaL JH HA' O 1 -((5)-8-chlorochroman-4-yl)-3-(l -(1 - methylpyrrolidin-3-yl)-lJ7-pyrazol-3- yl)urea I JH H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - methyl-5-oxopyrrolidin-3-yl)-lJ7- 1 II fpyrazol-3-yl)urea y 1 H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - methyl-5-oxopyrrolidin-3-yl)-lJ7-CIV XY / ’X\AIAN / pyrazol-3-yl)urea y j H H Ac (5)-l-(8-chlorochroman-4-yl)-3-(l-(4- 0 (methylsulfonyl)pyridin-2-yl)-lJ7- 0=^0pyrazol-3-yl)urea~~v # || J H HINIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure (. S’)- 1 -( 1 -(4-(2-aminopropan-2-yl)-3 - 0 (methylsulfonyl)phenyl)-l / 7-pyrazol-3- O=V_ O'Y 0 / == / yl)-3-(8-chlorochroman -4-yl)urea|| J H H NH2(5)- 1 -( 1 -(4-( 1 -aminocy clopropyl)-3 - 0 (methylsulfonyl)phenyl)-l / 7-pyrazol-3- 0=V_ yl)-3-(8-chlorochroman -4-yl)urea crA0VX / ^\ fx [ J H H NH2(. S’)- 1 -( 1 -(4-(3 -aminooxetan-3 -y 1 )-3 - 0 (methylsulfonyl)phenyl)-l / 7-pyrazol-3- 0=X crA o / Xro yl)-3-(8-chlorochroman -4-yl)ureaClYv '’N[ J H J\NH / \ NH2(5)-l-(l-(6-amino-5-(methyl- 0 sulfonyl)pyri din-3 -yl)- 1 / 7-py razol -3 -y 1)- 0=X 0 r==\ / = / 3-(8-chlorochroman -4-yl)urea| J H HN(5)- 1 -(8-fluorochroman-4-yl)-3 -( 1 -(4- 0 methoxy-3 -(methyl sulfonyl) phenyl)- LH- 0=X o r^\ / = / pyrazol-3-yl)ureaF 1 \ JJ 'Ac / [1 1H H2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)- 1 / Z-pyrazol- 1 -yl)-A,7V,4- cr'A o ^ Vi / trimethylpentanamide CI 1 J I X / NV* \[I J H H _ / 2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)- 1 / Z-pyrazol- 1 -yl)-A,7V,4- OA 0 r^\ trimethylpentanamide ci 1 J I X / M* \ J J H H _ / 2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)-U / -pyrazol-l-yl)-3-hydroxy- M / f-dirnethylpropanarnideCI / U-..NA X VxljH HHO-48- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 1Chemical Name Structure 2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -y l)-3 -hydroxy- o Vi / A, A-dimethylpropanamide CI i J 1 X \UH HHO(5)-2-(3-(3-(8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)-A- methylacetamide c. V""" N^N^NII 1 H H(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-A- O o o / X^| o °v K-N / H cyclopropylacetamide CL / X, JIO^)H H(5)- 1 -( 1 -(2-(azetidin- 1 -yl)-2-oxoethyl)- 0TZ TZU / -pyrazol-3-yl)-3-(8-chlorochroman-4-cr'V ° J^NC> yl)urea h X°°IZ TZ II JH H(5)-l-(8-chlorochroman-4-yl)-3-(l-(2- o morpholino-2-oxoethyl)- 1 / / -py razol -3 - O V / yl)urea CL X X JL A / \ / II 1H H(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl )-A -methyl -AT- c, Fi i r / X z-\ (pyridin-2-ylmethyl) acetamide[1 I H H(5)-l-(8-chlorochroman-4-yl)-3-(l-(2- 0 oxo-2-(piperidin- 1 -yl)ethyl)- 1 / / -pyrazol - 3-yl)urea c. V|| 1 H H(5)-l-(8-chlorochroman-4-yl)-3-(l-(2- oxo-l,2-dihydropyridin-3-yl)-lJ7- pyrazol-3-yl)urea(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -( 1 - methyl-2-oxo- 1,2-dihydropyri din-3 -yl)- l / / -pyrazol-3-yl)urea-49- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure (5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2-(4- methylpiperazin- 1 -yl)-2-oxoethyl)- 1H- pyrazol-3-yl)urear l|h h(5)-4-(3-(3-(8-chlorochroman-4- 0^1 o, Z-\ o yl)ureido)- UZ-pyrazol- 1 -yl) cyclohexane- ci 1 J 11 JL N- — ( \ / / 1 -carboxamide || 1 H H NH2(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl) piperidine- 1 - carboxamide T 1 H H NH2O o o(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -( 1, 1 - dioxidotetrahydro-2H-thiopyran-4-yl)- l / / -pyrazol-3-yl)ureaIZ IZ IZ1 -((5)-8-chlorochroman-4-yl)-3 -(1 -(1, 1 - h h°°di oxidotetrahydrothi ophen -3 -yl)- 1H- IZ IZ IZpyrazol-3-yl)urea1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1, 1 - di oxidotetrahydrothi ophen -3 -yl)- 1H- pyrazol-3-yl)urea ^ T•’o° (5)-l-(8-chlorochroman-4-yl)-3-(l-(4- (dimethylamino)cyclohexyl) -1H- pyrazol-3-yl)urea H J H H \ (5)-A-(4-(3-(3-(8-chlorochroman-4- O cr > o. k _ yl)ureido)- UZ-pyrazol- 1 -yl)cyclohexyl)- N-m ethyl acetami de || 1 H H —x(5)-A-(4-(3-(3-(8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 - yl)cyclohexyl)acetamide|| \ H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- omethoxypyridin-4-yl)-l / / -pyrazol-3- CL 1 1 JI / V yl)ureah l H H '== / -50- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure(5)-A-(2-(3-(3-(8-chlorochroman-4- f 0X* yl)ureido)- UZ-pyrazol- 1 -yl)ethyl)-7V- A methylacetamide1 J H I Z H Q QI Z4 °1 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1 / / -py razol - ZT ZT3-yl)-3-((5)-8-chlorochroman-4-yl)ureaC C——o O o1 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1 / / -py razol - 6 63-yl)-3-((5)-8-chlorochroman-4-yl)ureaIZ IZ IZ7V-(3-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl) IZ IZ IZacetamideJ J))7V-(3-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)cyclohexyl)acetamide7V-(3-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl) Ck J. \ JL / -UM' * ) acetamideuA 7V-(3-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)cyclohexyl)acetamide(5)-l-(8-chlorochroman-4-yl)-3-(l-(4- (methylamino)cyclohexyl)-lJ7-pyrazol-3- yl)urea || H H-51- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO 1 Z - z.-xJ Table 1Chemical Name Structure i Yi Y (5)-7V-(2-(azetidin- 1 -yl)ethyl)-4-(3 -(3 -(8 - chlorochrornan-4-yl)ureido)-l / / -pyrazol- 001-yl) benzamideQy (ZI ZI4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l -cyano- 44 ° °ZT ZT2-methylpropyl) benzamide4-(3-(3-((5)-8-chlorochroman-4- o oyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(l - O Ocyanopropyl)benzamide4-(3-(3-((5)-8-chlorochroman-4- IZyl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l - cyanopropyl)benzamide M H H IZ — ' HN— ^} z4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l - cyanopropyl)benzamide M H H — / HN— Q(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-((l - methoxycyclopropyl)methyl) benzamide(5)-4-(3-(3-(8-chlorochroman-4- o / =\ o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- (ethyl(methyl)amino)ethyl) benzamide [1 1H H4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- methoxypropyl)benzamideVxJH H—(5)-4-(3-(3-(8-chlorochroman-4- O. / =\ o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((3 - ci 1 J 11 \V Z \ methyloxetan-3-yl)m ethyl) benzamideH H—IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- fluorocy cl opropy 1) m ethy l)b enzami de I JH H— HN^.£>—F4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- fluorocy cl opropy 1) m ethy l)b enzami de fl ] H H — HN— \£>—F4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- fluorocy cl opropy 1) m ethy l)b enzami de fl ] H H — HN— \£>—F4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- fluorocy cl opropy 1) m ethy l)b enzami de fl ] H H — HN— \£>—F(5)-7V-(bicyclo[ 1.1.1 ]pentan- 1 -yl)-4-(3 - (3 -(8 - chi orochrom an-4-y l)urei do)- \H- °^i0° pyrazol-l-yl) benzamide I JH H— HN_ / \4-(3-(3-((5)-8-chlorochroman-4- o / =\ o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- ci 1 J U L. N- — A \_ / / (dimethylamino)propyl) benzamide l| 1 H H HN — v * t o H 4-(3-(3-((5)-8-chlorochroman-4- O / =\ o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- ci 1 J U L. \_ / / (dimethylamino)propyl) benzamide l| 1 H H HN — v * t o H 4-(3-(3-((5)-8-chlorochroman-4-? r===\i / "" A ° yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-((l - Qi 1 I JI Lr'J— 6 \ methylazetidin-2-yl)methyl) benzamide || J H H - ' HN— <4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l -CI><^V^^N^NX^S>N / ~ V_y \ / cyanopropan-2-yl)benzamide 11 ) H H - - HN— / \ — =NIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 1Chemical Name Structure4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l -clvV^NANAr V / \ / cyanopropan-2-yl)benzamide T| T H H HN^ / \ — =N (5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-((l -CIVV''’ZZN' \__y ~C cyanocyclopropyl)methyl) benzamide [I \ H H — ' HN^— =N4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- cyanocyclopropyl)methyl) benzamide o o4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-((2,2- difluorocyclopropyl)methyl) benzamide T| T IZ H H —7HN—.h°IZ(5)-A-((l -aminocyclopropyl) methyl)-4- o o(3-(3-(8-chlorochroman -4-yl)ureido)- 1 / / -pyrazol - 1 -yl)benzamideH HHN^^NH2A-((2-aminocyclopropyl)methyl)-4-(3-(3- (CS')-8-chlorochroman-4-yl)iireido)-l / / - pyrazol-l-yl)benzamide zz 2 I LJ _ _ (5)-4-(3-(3-(8-chlorochroman-4- ZZ? rZi / ^\ ° yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((3 - ci JL J JLv Z \ cyanooxetan-3-yl)m ethyl) benzamide H H -N(S)-N-((3 -aminooxetan-3 -yl)methyl)-4- ZZ? / "" A °(3-(3-(8-chlorochroman-4-yl)ureido)-U / - (21 1 I JI L N - h VZ \ _pyrazol-l-yl)benzamide H H H \N^^NH2(5)- 1 -( 1 -benzyl- l / / -pyrazol-3 -yl)-3 -(8- methylchroman-4-yl)urea °XZ °L JH HLZIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure(. S’)- 1 -(6-fluorochroman-4-yl)-3 -( 1 - phenyl- l / / -pyrazol-3-yl)ureaII 1 H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - hydroxy cyclopentyl)- UZ-pyrazol -3- Cl *1yl)urea || J H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -(1 -(3 - o r^\hydroxy cyclopentyl)- UZ-pyrazol -3- CL J. 1. X \ *1yl)urea || J H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - crX o Y=\hydroxy cyclopentyl)- UZ-pyrazol -3- GL Y X 1 N N Nyl)urea || J H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -(1 -(3 - oX o Y\hydroxy cyclopentyl)- UZ-pyrazol -3- Cl X 1 1. YXY|| X J N N Nyl)urea H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -(1 -(3 - cX o Y=A / \hydroxy cyclopentyl)- UZ-pyrazol -3- Gk 1. X XXyl)urea || J H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -(1 -(3 - 0 rs==\hydroxy cyclobutyl)- UZ-pyrazol -3- ck \ 7— OH yl)urea | H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -((15, O^^i 03R)-3 -hydroxy cyclobutyl)- l / / -pyrazol-3-ck JL YUK / ~ \ A— OH yl)urea | H H(5)-4-(3-(3-(8-chlorochroman-4- 9^4 oyl)ureido)- 1 / / -pyrazol - 1 -yl)benzoic acid Ck 1 J. U / / 0HXl J H H4-(3-(3-((5)-8-chlorochroman-4- O'^k 0 H yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-(((A)- 1 -ck 1 J II / N — XNx methylazetidin-2-yl)methyl)benzamide. v.nv>iIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(((5)- 1 - O'A o H A CL 1 J IJ / N - / \| methylazetidin-2-yl)methyl)benzamide (V s. V. » A ( (5)-5-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((3 - CL / i / 1. Z AN N Z / / \ methyloxetan-3-yl)methyl)picolinamide H H N HN—(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V,7V- °A ° [A / - \0ClN N N dimethylpiperidine-1 -carboxamide H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -( 1 - A0X\ / — \ (ethylsulfonyl)piperidin-4-yl)-l / / -0pyrazol-3-yl)urea A A A -A(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- methylpiperidine-1 -carboxamide | H H - ' NH1 -( 1 -( 1 -acetylpyrrolidin-3 -yl)- 1H- pyrazol-3-yl)-3-((5)-8-chlorochroman-4- a AO- A XA"! yl)urea1 -( 1 -( 1 -acetylpyrrolidin-3 -yl)- 1H- pyrazol -3 -y 1 ) -3 -((5)-8 -chlorochroman-4- ciXO.yl)urea A) H » ^"^0 1 -( 1 -( 1 -acetylpiperi din-3 -yl)- U7-pyrazol- 3 -y 1 ) -3 -(CS')-chrom an -4-y l)ureaA i Z 1. A J AAl A \. / H H1 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1 / / -py razol - crA O,3-yl)-3-((5)-chroman-4-yl)ureaz 1 A J. -IA A^IAAI \ _ / }H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 1Chemical Name Structure (. S’)- 1 -(chroman-4-yl)-3 -(1 -(2-(pyridin-4- yl)ethyl)- 1 / / -py razol -3 -yl)ureaCO H HN N N(5)-2-(3-(3-(8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -yl)-A- O V-MH ethyl acetamide Cl 1.H Ho(5)-2-(3-(3-(8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-ethyl-A- methylacetamide Cl J. 1 JJ\ \ NXv '-'N / XN / XNH H1 -((5)-8-chlorochroman-4-yl)-3 -(1- O^X °^ O / . ((lA,45)-4-(dimethylamino)cyclohexyl)- CL 1 1, JL \ >. N l / / -pyrazol-3-yl)urea I H H - ' \ (5)-2-(3-(3-(8-chlorochroman-4- OH yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-(2- hydroxyethyl)acetamide 0 _ / ci ’. N HNo Iif JH H(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-A-(2- hydroxyethyl)-A-methylacetamide(5)-l-(8-chlorochroman-4-yl)-3-(l-(2- Cl(pyridin-4-yl)ethyl)-lJ7-pyrazol-3-yl)ureaCOH^ NNIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3-(l-(4- (methylamino)cyclohexyl)-l / / -pyrazol-3- yl)ureac|\AJ. AN vHH H —7V-(4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)cyclohexyl)- N-m ethyl acetami de A l JLH H AA -y-^ \(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -( 1 - crA0NA (methylsulfonyl)piperidin-4-yl)-lJ7- / - — \ o GL J. 1, A / Lr \ NA— pyrazol-3-yl)urea [1 J H H 8methyl (5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)piperidine- 1 - A / O A AA V carboxylate H H - 0 _ (5)-2-(3-(3-(8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)acetic acid 0 / " N] 0 rzz=\ A-OH CL A\ \ AH H4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- UZ-pyrazol- 1 -yl)-7V-(l -C|? A\ANA A0A> AA / N cyanopropyl)benzamide n A. AA / NA nN—7V-(4-(3-(3-((5)-8-chlorochroman-4- 0 0""" A 0 p==\ - _ yl)ureido)- UZ-pyrazol- 1 - yl)cyclohexyl)acetamide ■ A? ■[1 JH H1 -(8-fluorochroman-4-yl)-3 -( 1 -(4- methoxy-3 -(methyl sulfonyl)phenyl)- 1H- V pyrazol-3-yl)urea o 0 N\ / xF\ / NL / ANA'NA'' N N / \ / h \ H H -IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 1Chemical Name Structure1 -( 1 -(4-(2-aminopropan-2-yl)phenyl)- 1 1 9 A\. W NHn U / -pyrazol-3-yl)-3-(8-chloro-6- CL / X. JA JL / XK, / A AA fluorochroman-4-yl)urea H H - \1 -( 1 -(4-(2-aminopropan-2-yl)phenyl)- 1 / / -py razol -3 -y 1 )- 3 -(chroman-4-yl)urea / 1VV Z r A^ N. A' x Nx Z / ) — ANH2H H y _ / / \ '?■1 -((47?)-8-chl oro-2 - (methoxymethyl)chroman-4-yl)-3-(l- phenyl-l / / -pyrazol-3-yl)ureaOA 0 _ _Cl\ / X A A JZB J H H1 -((47?)-8-chl oro-2 - (methoxymethyl)chroman-4-yl)-3-(l- phenyl-l / / -pyrazol-3-yl)ureaCl\ A A JZB J H HV= / 1 -((47?)-8-chl oro-2 -0H(hy droxymethyl)chroman-4-yl)-3 -( 1 - phenyl- l / / -pyrazol-3-yl)ureaCI^JZ A A(| J H Hl-(8-cyanochroman-4-yl)-3-(l-phenyl- l / / -pyrazol-3-yl)ureaNx ■A A --' A M / AN' A M / A A X- / H H- (5)- 1 -(8-chlorochroman-4-yl)-3 -(1- R D (phenyl-t / 5)-l / / -pyrazol-3-yl)urea ° V ° r^\ AAcW AAAAA Z JH HD - ZIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0130] In another aspect, provided herein is a method of treating PMD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by formula (II):Formula (II)or a pharmaceutically acceptable salt thereof, wherein:Xi - X3 are independently carbon or nitrogen;Ri is independently selected from the group consisting of hydrogen, halogen, cyano, and OCH3;R2 is selected from the group consisting of hydrogen, halogen, cyano, Ci-Ce alkyl, C(O)ORe, C(O)NReR7, cycloalkyl, heterocyclyl, aryl, C(O)Re, ORe, and heterocyclodiene;wherein Ci-Ce alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, NH2, halogen, methyl, C(O)NReR7, SO2R6, ORe, heterocyclyl, cycloalkyl, NHC(O)Re, CF3, and NHS(O)(O)Re;wherein aryl is optionally substituted with one or more groups each independently selected from the group consisting of SO2R6, CCH3CH3NH2, NH2, and C3H5O;wherein heterocyclyl is optionally substituted with one or more groups each independently selected from the group consisting of C(O)Re and OH;wherein heterocyclodiene is optionally substituted with Ci-Ce alkyl;R3 is absent, hydrogen, C1-C4 alkyl, or halogen; wherein C1-C4 alkyl is optionally substituted with one or more groups each independently selected from the group consisting of OH, C(O)Re, halogen,or R2 and R3 are interconnected to form a five-member heteroatom ring;R4 and R5 are each independently absent or hydrogen;Re is H, methyl, ethyl, C3-6 cycloalkyl, CH2C(O)NH2, or CH2C(O)OCH2CH3;-60- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOR7is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2OR6; and Vn is 1-4; and *denotes a chiral carbon.ZI

[0131] In some embodiments, a compound is a compound listed in Table 2.< o=ziTable 2Chemical Name Structure(S)- 1 -(8-chlorochroman-4-yl)-3 - (IZ / pyrrolof C—3,2-Z>]pyridin-5-yl)ureao2(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- / methylpyridin-2-yl)ureaCh ZVo / X A J!x • 'N LJ N | l" N'(S)- 1 -(8-chlorochroman-4-yl)-3 - (pyridin-2- yl)urea) Z / / / x \fiS9-6-(3-(8-chlorochroman-4- yl)ureido)-N-methylpicolinamide L zi V N N N KI. I. JH Hi fiS9-6-(3-(8-chlorochroman-4- yl)ureido)picolinamide0fiVCIYV 'NANX VH* UH Ho fiS9-6-(3-(8-chlorochroman-4- yl)ureido)-N, N-dimethylpicolinamide C'YV'NV? nNX1- MH HoIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 2 / Chemical Name Structure o o / f59-l-(8-chlorochroman-4-yl)-3-(5-xY CkA 0 / 'o (hydroxymethyl)pyridin-2-yl)ureacu / L A A H\ / — £.V VN NN H I H ( o H J=(AJ-l-(5-acetylpyridin-2-yl)-3-(8- o chlorochroman-4-yl)ureaN NH(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- O(A k 0ethoxypyridin-2-yl)ureack A IK..£1 XJ N N N 0H H(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- 0'cyanopyridin-2-yl)ureaCKA- \ ~K 'N'JJHf$-l-(6-(lH-imidazol-2-yl)pyridin-2- 0'yl)-3-(8- k ° fl H chlorochroman-4-yl)urea K 'N v 'N'y H H k z‘Z N-A f59-6-(3-(8-chlorochroman-4- o'yl)ureido)- A J3 -methylpicolinate CK A r 'N NJ H HcfiS9-6-(3-(8-chlorochroman-4- 0" A oyl)ureido)-3- ck A J.methylpicolinic acid Y' 'N' 'JHNH ■ N1'Y. 00HIfiS9-6-(3-(8-chlorochroman-4- o'yl)ureido)-N, N,3- 1Ck A \, N.. trimethylpicolinamide Y '"'hA V’ N 'ir:.1HH ir '0IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 2Chemical Name Structuref59-l-(8-chlorochroman-4-yl)-3-(6- CfA 0 cyclopropoxypyridin-2-yl)urea ci A. A n[I N" 0 A1 N(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- (pyrrolidin- CL,. A J, A1 -yl)pyridin-2-yl)urea ' 'N N ' 'N' 'N"'\H Hu / l-(f59-8-chlorochroman-4-yl)-3-(6-(2- cAA o < hydroxypropyl)pyridin-2-yl)urea< A; N NH i H HorCA h V A 'Y N V NH I H Hf59-2-(6-(3-(8-chlorochroman-4- O'"yl)ureido)pyridin-2-yl)acetamide ci, A > 1 1A r 'N N'H HAethyl f59-2-((6-(3-(8-chlorochroman-4- o" A o AA yl)ureido)pyridin-2-yl)oxy)acetateCK / L J Jk A X YY N N N ro I H H 1M1 f59-2-((6-(3-(8-chlorochroman-4- o'' '"i Oyl)ureido)pyridin-2-yl)oxy)acetamide CL. [I.1 1 A,, „o N O Y' H bA" NH2(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- oA0cyclopropylpyridin-2-yl)urea ci, A J, A JA N•Q a a(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- c(hydroxymethyl)pyridin-2-yl)ureaClx J '"1 Hx''i\A N'' A-™[1 H HX.IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 2_ Chemical Name Structure(S) - 1 -(chroman-4-yl)-3 -(6- 0 (hydroxymethyl)pyridin-2-yl)urea\ / . AXZ, OH N[1 J H H(S)- 1 -(6-acetylpyri din-2 -yl)-3 -(8- chlorochroman-4-yl)ureal-(fiS9-8-chlorochroman-4-yl)-3-(6-(l- O^Y0XX hydroxyethyl)pyridin-2-yl)urea>1 Y N N N T|l \ H H | oor / O^Y 0 YYCIY \Y|l Y J Y_H z HNYYz |-0HfiS9-6-(3-(8-chlorochroman-4- o '" i 9 [yl)ureido)-N-(2- " X1Cl A.hydroxy -r "k LY • X Ax Nethyl)-N-methylpicolinamide N N N Y OH |l, J H H bfiS9-6-(3-(8-chlorochroman-4- yl)ureido)-N-(2- ci- AxJ-- A A "■]H(dimethylamino)ethyl)picolinamide Y V 'N N|l J H HN';'N'01fiS9-6-(3-(8-chlorochroman-4- O' - 0 ryl)ureido)-N-(2- Hci-,1 J- A J hydroxyethyl)picolinamide k N N N Y OH U JH Hb(AJ-N-(2-amino-2-oxoethyl)-6-(3-(8- 0 ft i o chlorochroman-4-yl)ureido)-N- cixA -X A A methylpicolinamide Y Y N N " N' T| NH2|l J H H0fiS9-6-(3-(8-chlorochroman-4- 1 OH yl)ureido)-N-(2- ci X J Ji ihydroxy-2-methylpropyl)-N- Y'’ Y ' ~ N ' N '• A Y< |l J H H )imethylpicolinamide0-64- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO o T z O o— Table 2 < Chemical Name Structure / > \ <. f59 6 ( - 8 c l r c r m n IZ TZ- - 3 ( - h o o h o a -4- O'A 0yl)ureido)-N-(2- Ao A°A N., (dimethylamino)ethyl)-N- “'A ' B'Y N YxZXNZVz / / / AA m thy pic linamide z Ae l o \ / 6 i f59-6-(3-(8-chlorochroman-4- ziyl)ureido)-N-(2- O'A 7T 0C zxcyanoethyl)-N-methylpicolinamide k 1 J, A J Q ix ’" A 'NN' N Y "" CN LA \ / AH0 / \f59-6-(3-(8-chlorochroman-4- \ / °yl)ureido)-N-(2- methoxyethyl)picolinamide o6-(3-(f59-8-chlorochroman-4- O'A 0 ryl)ureido)-N-((AJ- l-hydroxypropan-2-yl)picolinamide V N N|l 1 H H6-(3-(f59-8-chlorochroman-4- yl)ureido)-N-((AJ- oA o (A j2-hydroxypropyl)picolinamide W N N|| J H H6-(3-(f59-8-chlorochroman-4- (AA 0 ryl)ureido)-N -((R) - ^1Hl-hydroxypropan-2-yl)picolinamide ^<yNYzx°Ho • 6-(3-(f59-8-chlorochroman-4- O" A 0 Ifyl)ureido)-N -((R) - ck A J. A J-t "'IHI 2-hydroxypropyl)picolinamide 'N<' 'YN'K'XX° I. J ■'H0(AJ-N-(3 -amino-3 -oxopropyl)-6-(3 -(8- 0chlorochroman-4-yl)ureido)-N- ci- A. J,. NH2methylpicolinamide I T H HNY K 0 0 (AJ-l-(chroman-4-yl)-3-(lH- H pyrrolo[3,2- [prN> b]pyridin-5-yl)ureaH-65- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 2Chemical Name Structure1 -((S) -8-chlorochroman-4-yl)-3 -(5 -( 1 - hydroxyethyl)pyridin-2-yl)urea0^ 0Qi JL J. JI J.V [1 X JVN N NH H5J-8-chlorochroman-4-yl)-3-(6-(2,2,2- o^ otrifluoro- 1 -hydroxy ethyl)pyridin-2- F yl)urea ClxJx ifJ.. N A N X N X-X FH HOHor O^X 0 F cix XJ^LITX N A N X N XA<FF HnHO1Hf59-l-(8-chlorochroman-4-yl)-3-(6- ((methylsulfonyl)methyl)pyridin-2- yl)urea ci33.,NANJC15r [1 J H H01 -(6-{(R)- 1 -acetylpiperi din-3 - oyl)pyridin-2-yl)-3- (8-chlorochroman-4-yl)urea > [7I X J' N N N JH H 1 X J or °"^X 0UH HU NQ-^IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 2Chemical Name Structure / \ 6-(3 -(7 -cy anochroman-4-yl)ureido)-N - methylpicolinamide O'"'"""'-] OAx x l Y AHNHSA \””” xJI JxNY ' 0 / .hA X \.ZT(AJ-6-(3-(7-cyanochroman-4- yl)ureido)-N-methylpicolinamide oA o(TA H A A.A I / AI \ J N NH H N' Y - 0 _ / o(7? J-6-(3-(7-cyanochroman-4- yl)ureido)-N-methylpicolinamide O'" A 0AA A ( X H J AY]| J N H N H0 lAf59-6-(3-(7-chlorochroman-4- yl)ureido)-N-methylpicolinamide o 1A J o rH u 1J AI / 1 N N N YH Ho (7? J-6-(3-(7-chlorochroman-4- yl)ureido)-A-methylpicolinamide oA o AY I-I f Ai AA N AN A N X YI A JH Ho l-(f59-8-chlorochroman-4-yl)-3-(6- W-3- hydroxypyrrolidin- 1 -yl)pyridin-2- yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 2Chemical Name Structurel-(f$-8-chlorochroman-4-yl)-3-(6- (.(S)-3- O YY hydroxypyrrolidin-l-yl)pyridin-2- yl)ureac 1" " N N ■ hr " N ■ \OH(S) - 1 -(6-(4-(2-aminopropan-2- yl)phenyl)pyridin-2-yl)-3-(8- o''-'-, o f’Ai chlorochroman-4-yl)ureaU H HNX I, TNH2 1 - (6 - ( (S) - 1 -aminoethyl)pyridin-2-yl)-3 - o(-8- chlorochroman-4-yl)urea Of V N N N F[[ 1 H H |or oCk / L J:, A- JLW N N2[I I H H IN-((7? J- 1 -(6-(3 -(8-chlorochroman-4- <pi 9 n yl)ureido)pyridin-2-yl)ethyl)acetamideHCI'Y ’’V' 'N' '►k'N* 'TN'rk [1 JHH | g Ofci? " J ° fl. N, X J Tf F 'NT ¥ (S)- 1 -(8-chlorochroman-4-yl)-3 -(6-(2- methyl- 2Z / -l,2,3-triazol-4-yl)pyridin-2-yl)urea a. x X jlx,NTj 7 H HNt N”"~;NIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 2Chemical Name Structuref59-l-(8-chlorochroman-4-yl)-3-(6-(3- hy droxyoxetan-3-yl)pyri din-2 -yl)urea o' "1 Q A, □H Cl-xx-k J. A JX 'N‘:>AhT NK; H Hu(S)- 1 -(8-chlorochroman-4-yl)-3 -(6-(l - hydroxycyclopropyl)pyridin-2-yl)urea A o )H ck A 1 A 1 XS k 'N r i NxH I- 4o o ~ _ ul-(f59-8-chlorochroman-4-yl)-3-(5- fluoro-6-(l- hydroxyethyl)pyridin-2-yl)urea A M > i? IY 1'N 11^ 11 N k n nor j i JYro H " N 'NxN' kH HfiS9-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)-N, N- 0""" fA c ) dimethylacetamide ck / L ] L.A H H IfiS9-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)-7V- o''x) methylacetamide aXy ]Y6S)-6-(3-(8-chloro-6-methoxychrornan- 4- O'" k □ YA H yl)ureido)-A-methylpicolinamide j.. A X A' 'N N N -Nx H Hb-69- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 2Chemical Name Structurel-(f59-8-chlorochroman-4-yl)-3-(6-(l- 0^methoxyethyl)pyridin-2-yl)ureaCkzL ' f. - Ox ”N' N' N YH H XJ ar (A G oCK A A A J N N O H Hf59-6-(3-(8-chlorochroman-4-.-F yl)ureido)-3- O' G oTfluoro-A X AH-methylpicolinamide ClyA X N N -N- Y " j H F QA-ff59-l-(6-(3-(-8-chlorochroman-4- O^A 0yl)ureido)pyridin-2- yl)ethyl)methanesulfonamide x Y N N I X uN 7, SXl-l / JH H1 O' Of cxY oCL V A Y X I J, N..9N A N - L JHN' T X - H 1 0 f59-6-(3-(8-chlorochroman-4- yl)ureido)-A, Adimethylpyrazine- (A > 01 1 2-carboxamide CbyX^ J. I --N-- E FJlI L nJ N0 (S)- 1 -(8-chlorochroman-4-yl)-3 -(2- methyl- / 7 / pyrrolo[ cA]2,3-b]pyridin-6-yl)ureaL n| L n| H (S)- 1 -(6-(4-(3 -aminooxetan-3 - yl)phenyl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea CK Ghi HIJN1 II MH2A)-70- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 2Chemical Name Structure(S)- 1 -(2-acetylpyrimidin-4-yl)-3 -(8- k 0 k chlorochroman-4-yl)ureaJ. u 1!,x, '-N" 'N" 'N' Y H H II l-(f59-8-chlorochroman-4-yl)-3-(2-(l- hydroxyethyl)pyrimidin-4-yl)urea A 0 AA / \\ \ / (k o> '.. j-i A x / w " N hr N' Y H Ha O1H T Ql-(f59-8-chlorochroman-4-yl)-3-(2-(l- \ / z= _,hydroxyethyl)pyrimidin-4-yl)urea V <o / \\ / > o AN\ / O\) < \— / 5. / > / — \\ \ ■■ 1 A 1 A / ' 'N N' N YH H OH or " Y o fA’N k A A J. z r 'N' 'N‘ N' 'T H H1OH(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- H methyl- / / / -pyrrolo[3,2-b]pyridin-5-yl)urea ck A -X, A A X-- / " A K N N N|... 1 j H Hl-(f59-8-chlorochroman-4-yl)-3-(2- (2,2,2- cA o AN F trifluoro-1 -hydroxy ethyl)pyrimidin-4- Ck X I JI A X,kFyl)urea 'K 'N N N' Y F JH Hu OnH (S)- 1 -(8-chlorochroman-4-yl)-3 -(2-(2- methyl- 2H-l,2,3-triazol-4-yl)pyrimidin-4- Ck A 1 A X A, N yl)urea Y A 'N N’ N A ki—H H LIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOChemical Name Structure(lS)-l-(8-chlorochroman-4-yl)-3-(6-(2- methyl- •"x Nx0 'i 0 A j2H- 1,2,3 -triazol-4-yl)pyrazin-2-yl)urea ci- Y -L|l Y 1" J-L Jx i •x, N 'N' N ¥H H r N—(S) - 1 -(8-chlorochroman-4-yl)-3 -(4-(2- methyl- O'xi 0 hT'2H- 1,2,3 -triazol-4-yl)pyrimidin-2- >1 yl)urea Ck A V X. N A N A N J)l-t JH H(S) - 1 -(8-chlorochroman-4-yl)-3 -(6-(4- (methylsulfonyl)phenyl)pyridin-2- yl)urea CK A A, A A AC j H HN‘ Q / A 0 "0

[0132] In another aspect, provided herein is a method of treating PAID in a subject in yneed thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by formula (III):11or a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, C]-C3alkyl, Cl, F, CN, and O-Ci-C6alkyl optionally substituted with one or more halogen;R2is H or C1-C3 alkyl optionally substituted with OR5;-72- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOR3is each independently H or C1-C4 alkyl optionally substituted with one or more halogen or OH;R4is OR' or S, wherein one R4is OR5and the other R4is S;Z is selected from the group consisting of Ci-C6alkyl, Ci-C6alkene, NR^R6, SR5, C(O)R5, C(O)R7, C(O)OR5, C(O)NR5R6, cycloalkyl, heterocyclyl, and, heteroaryl, heteroaryl-cycloalkyl, aryl -heterocyclyl, aryl -heteroaryl, and sulfonamide, wherein the (1) C C6alkyl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more halogen, phenyl, OR5, halogen, C(O)NR5R6, NR5R6, NR5-C(0)CH3, SO2R5, NH-SO2R5, heterocyclyl, aryl, heteroaryl, and aryl -heteroaryl, (2) cycloalkyl is optionally substituted with one or more groups each independently selected from the group consisting of F, Ci-C3alkyl-OH, C C3alkyl-O-Ci-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and NR5-C(O)CH3, (3) heterocyclyl optionally contains another heteroatom that is N or O, and is optionally substituted with one or more groups each independently selected from the group consisting of F, OR5, keto, C3-C6cycloalkyl, C(O)CH3, C(O)NR5R5, NH- C(O)R5, NH-SO2R5, and C C4alkyl that is optionally substituted with one or more F or OH, (4) aryl is optionally- substituted with one or more groups selected from the group consisting of: (i) C1-C4 alkyl that is optionally substituted with one or more groups each independently- selected from the group consisting of F, OH, and NR’R6, (ii) C3-Cg cycloalkyl that is substituted with NR5R6, halogen, CN, OR5, C(O)NR5R6, NR5R6, SO2R6, SO2NR5R6, SO(NH)R5, S(NR)(NH)R5, P(O)R5R5, and (iii) 4- or 5,6-membered heterocyclic ring optionally containing one or more additional heteroatoms that is S or N, and is optionally substituted with one or more groups independently selected from the group consisting of F, Cl, OR5, CN, C]-C4alkyl, oxo, andNR5R6, (5) heteroaryl is optionally substituted with one or more groups each independently selected from the group consisting of cycloalkyl optionally substituted with one or more OH or F, CN, C(O)NR3R6, OR5, NR’R6, oxo, SO2R6, a 4- to 6-membered heterocyclic ring, and Ci-04 alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR'R6, OR5, and C(O)NR5R6; (6) aryl -heterocyclyl is-73- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOoptionally substituted with one or more groups each independently selected from the group consisting of Cl, F, and C1-C4 alkyl that is optionally substituted with a group selected from the group consisting of OR5, Cl, and F; and (7) aryl -heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5;R3is independently H or Cj-Cs alkyl;R6is selected from the group consisting of H, cyclopropyl, and C]-C5alkyl optionally substituted with one or more groups selected from the group consisting of NR5R3, OR3, and halogen;R7is cycloalkyl optionally substituted with one or more halogens; 11 is 1-4;Op is 1-2; ywith the proviso that a compound is not / \. ~ selected from the group consisting of: / A(S)-l-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2 / f-pyran-4-yl)thiazol-2-yl)urea, 1 -(chroman-4-yl)-3 -(4-cycl obutylthi azol-2-y l)urea,l-((3A,47?)-3-(hydroxymethyl)chroman-4-yl)-3-(4-(methoxymethyl)thiazol-2-yl)urea, and1 -(5 -cy cl opropylthi azol-4-yl)-3 -((3 A,4A)-3 -(hy droxym ethyl)chroman-4-yl)urea.

[0133] In some embodiments, the compound of formula (III) is a compound listed o in Table 3.Table 3Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3- (2- (1 -hydroxy ethyl)thiazol-4- yl)ureal-((S)-8-chlorochroman-4-yl)-3-(2- Q((R)- 1 -hydroxy ethyl)thiazol-4-ZP o r"s. PH yl)urea CL. X A "nr •••• ■• ’'hr A N A PN 4 \cPh hIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 3 X A. Chemical Name Structure JsJ Z r 1 -((, S)-8-chlorochroman-4-yl)-3- (2- O''(1 -hydroxy ethyl)thiazol -4- yl)urea 1? OZOH CK A. J--. A A r A^-A -< A A ' j AJ H HVAch A1 -((S)-8-chl orochrom an-4-yl)-3-(2- (A "'1 \ X 0frs OH ((S)- 1 -hydroxy ethyl )thi azol -4-yl)urea A oC!.. J. J4 Jl"" N ” N " A \ I / A H1H1 -[(45)-8-chlorochroman-4-yl]-3- [2- A o- o / T'S (dimethylaniino)thiazol-4- yl]urea. ( \ / Q / y. 'A.. A. A A1A (Ox / ■, y W N"XN \ A / / \H Hl-[(4, S)-8-chlorochroman-4-yl]-3- 14-[4- ) 0 S' "'A H [pyrrolidin-2- yl]phenyl]thiazol-2- J. JI k A / A yl]urea A v A A / H Hl-[(4S)-8-chlorochroman-4-yl]-3- [4-|4- [pyrrolidin-2- yl|phenyl]thiazol-2- Clx,yl]urea1 -(2-(l -(2-aminopropyl)- IHpyrazol- 1 0; - ' SN..... *..3-yl)thiazol-4-yl)-3-((5)- J.. A J ¥ T 8-chlorochroman-4-yl)urea N 'N 'N NN?N. H H1 -(2-(l -(2-aminopropyl)- IHpyrazol- O''"'”'3-yl)thiazol-4-yl)-3-((5)- k 1 1 > A ¥ T 8-chlorochroman-4-yl)urea 'N' 'N' N NH2H H(5)- 1 -(8-chlorochroman-4-yl)-3 - O'A O - s(2-( 1 -ethyl- 1 H-py razol -4-y 1 )thiazol-4-yl)urea CK A J. A 1 VxIF A 'N hT N AN (S)-l-(8-chlorochroman-4-yl)-3- (2- (pyridin-2-yl)thiazol-4-yl)ureaci-^.IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure(S)-l-(8-chlorochroman-4-yl)-3- (2- — S(pyridin-4-yl)thiazol-4-yl)urea 0 fC ^l'•^x A-^s^x X A -N4- 'A U J H HN(5)-l-(8-chlorochroman-4-yl)-3- (2- phenylthiazol-4-yl)urea oA o.-ACK A A A A AX Y Ar N N‘ ‘N w N J H H(S)- 1 -(8-fluorochroman-4-yl)-3 -(2- phenyithiazol-4-yl)urea DC o rAN \= / || J H H(. S')- 1 -(chroman-4-yl)-3 -(2 -phenylthiazol-4-yl)ureaA A I X V X / N A- / z| 1 H H(5)- 1 -( 8 -chlorochroman-4-yl)-3 - (2- (pyridin-3-yl)thiazol-4-yl)urea0ITCI A A A y H J H H1 -[(45)-8-chlorochroman-4-yl] -3 - (2- cyclopropylthiazol-4-yl)ureaCK A ); A xXl-[(45)-8-chlorochroman-4-yl]-3- [2-(l-methylpyrazol-4-yl)thiazol- 4-yl]urea cu / O A, A A. A A * V " V N 'N N|| J H H1 -[(45)-8-chlorochroman-4-yl] -3 - [2-(4- methylsulfonylphenyl) thiazol-4-yl]urea A A 9 FA-AA $ a Ux-. y x... x xX / jsjAx -NANXA As—H H 0IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-[(4, S)-8-chlorochroman-4-yl]-3- 12-[4- O''" '"(methylsulfamoyl) phenyl] thiazol-4- yl]ureaH H ’ 0 1 -[(45)-8-chlorochroman-4-yl] -3 - [2 -(3 - 0. / methylsulfonylpheny 1) thiazol-4-yi ] urea J O r-SCK A J- 4 llfi '■]' 'N' y / / X.HH4-[4-[[(45>8-chlorochroman-4- O'"yl]carbamoylamino]thiazol-2-yl]- N- 1 V 0s\ / \ HN- - CI-.. X J. A X ^-4 YA methyl-benzamidet Fj3 K FTI Pl U15-[4-[[(45)-8-chlorochroman-4- 0 'b 0 / 7~"~x MH— yl]carbamoylamino]thiazol-2-yl]- N- ci. X J- X X A-Xmethyl-pyridine-2 -carboxamide[I J H HNO l-[(45)-8-chlorochroman-4-yl]-3- [2-[3-0HN— (methylsulfamoyl) phenyl]thiazol-4- yljurea (X > o frxCk.. X., X A JL C J'N N N W / Y H Hmethyl 4-[4-[[(4S)-8- chlorochroman-4- F yl] carbamoylamino]thiazol -2-yl] -2- x " J s rV x xhn~~ fluorobenzoate CK X J-, JI X < Y-z |l J H H 0 4-[4-[[(45)-8-chlorochroman-4-yl] x o-~ carbamoyl amino] thiazol-2-yl]-2- O'"'1 V ii HN-- m eth oxy-benzamid e CK YN 'hf N V- / 1 H H “*■ O 4-[4-[[(4, S)-8-chlorochroman-4-yl] ocarbamoyIamino]thiazol-2-yI] CK X.. JI X \\ / ) — / " benzamide N 'N 'N Yx V u 1-1 H 0 4-[4-[[(4S)-8-chlorochroman-4- y 1 J carbamoylamino]thiazol-2-yl] - 2- methoxy-benzamideTi Y " N" " N Yy[1 J H H 0IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO N f X lx. lx.Table 3 y cu — / Chemical Name Structure4-[4-[|(45)-8-chlorochroman-4- z; - F yl]carbamoylamino|thiazol-2-yr|- 2- 0^' W ZC ffl uoro-benzamide Cl-. i f X VXY 'N' 'N' " N r V.- / '2 rV' H H O X / - l-[(45)-8-chlorochroman-4-yl]-3- [2-(l-methylpyrazol-3-yl) thiazol- A o4-yl]ureazx2 %1 -[(4tS)-8-chlorochroman-4-yi]-3- [2-(4- o y > ° O. '" A O YS'. cyanophenyl)thiazol-4- yl]urea CK X J, A 1 Hi J H H / Y / \5-[4-[[(45)-8-chlorochroman-4-yl] O'" / _carbamoylamino]thiazol-2- yljpyridine- Clx -X X- 2-carboxamideV Yo- 1 -[(4tS)-8-chlorochroman-4-yi]-3- [2-[ 1 - (2,2-difluoroethyl) pyrazol- 4- Ck. -4 >9 1 9 Y yljthiazol -4-yi]urea Y 'N' Y" " N VY F l-[(45y 8-chlorochroman-4-yl| -3- [2-[ 1 -(2,2,2-trifluoroethyl) pyrazol-4- ciyljthiazol -4-yi]ureax1 -[(4S)-8-chlorochroman-4-ylJ -3 - [2 -(5 - Q'V'- 0 P7-Sz^..^ cyano-2-pyridyl)thiazol-4- yljurea CK AYj Ay- A X 4 — 9' 4•N N' 'N 4 / / - N.-J H HN— ’ l-[(45)-8-chlorochroman-4-yI]-3- [2-[l - O"’A O, F (2,2-difluoroethyl) pyrazol- 3- ci. i J., x i? r yl]thiazol-4-yl]urea"" Y 'YN FX. JH H1 - 1 (45) -8 -chlorochroman-4-yl ] -3 - [2-[ 1 -(2,2,2-trifluoroethyl) pyrazol-3- yl]thiazol-4-yI]urea CK A A 44 U h J H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-[(4, S)-8-chlorochroman-4-yl]-3- 14-(4- cy anopheny I)thiazol -2- yl ] ureacixA A A K y-y \ Tj ’hr '■N YY H H( 1 - [(45)-8 -chlorochroman-4-yl] -3 - [4-(4-methylsulfonylphenyl) rYY O / Y ® thiazol-2-yl]urear, ° 1. V Y Y jh hl-[4-[4-(l-amino-l-methyl-ethyl)9'X ophenyl]thiazol-2-yl]-3-[(45)-8- CK,4. A y Y / chlorochroman-4-yl]urea YA Y.nY 'N' " N' " N V— / YNH24 o y Y Y H H '1 - [2- [ 1 - [2-aminopropyl]pyrazol-4- O? X"'v"' o r-Syl]thiazol-4-yl]-3-[(45)-8- Y / —CK A -J. jt A » Y ' Y chlorochroman-4-yl]urea 4 Y 'N'N"' 'NAN NH?4o™~1 - [2- [ 1 - [2-aminopropyl]pyrazol-4- O'"' Y O ySyl]thiazol-4-yl]-3-[(45)-8- CK X J- 1 I A / V Y chlorochroman-4-yl]urea Y A' 'N WN NH2YY H Hl-[(45)-8-chlorochroman-4-yl]-3- Y[2-[4-[pyrrolidin-2- i yl]phenyl]thiazol-4-yl]urea ck X X, A X > Y Y JXX Y 'Y N‘ 'N N W \* J YYH Hl-[(45)-8-chlorochroman-4-yl]-3- [2-[4-[pyrrolidin-2- 9 Y A A A A x yl]phenyl]thiazol-4-yl]urea CK< Y"MYY \ J ■\YH H1 -((S)-chroman-4-yl)-3 -(2-( 1 - hydroxyethyl)thiazol-4-yl)urea1 -((S)-chroman-4-yl)-3 -(2-( 1 - hydroxyethyl)thiazol-4-yl)urea? 9 n"s-OHJ.. H J! _[iVN" '•N"''" N \* Y H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO XTable 3 o! Chemical Name Structure / A (5)-l-(8-chlorochroman-4-yl)-3- (2- (pyrrolidin- 1 -yl)thiazoI-4- yl)ureaCK.X \1 -((S)-8-chlorochroman-4-yl)-3- (2-(3- M O"hydroxy-3-methyl pyrrolidine- 1 - yl)thiazol-4-yl)ureaJ X _ / \l-((S)-8-chlorochroman-4-yl)-3- (2-(3- O '" c — s. hydroxy-3 -methyl pyrrolidin- 1 - iyl)thiazol-4-yl)urea CK / X. " N" X 'N V- 1V-OH I / \9A 'z\ H n \ i Q \ J A v \,.1 -((5)-8-chlorochroman-4-y l)-3- (2-((< S1)- Q'" 'A V \ / \ / 3 -methoxypy rrolidin- 1 - yl)thiazol-4- yl)urea A JL ■w.1 J / --<f " TT 'N V. U " vo- " \ -’o.1 -((S)-8-chloroch roman-4-yl)-3- (2-((7?)- 0 • - X S3 -methoxypyrrolidin- 1 - yl)thiazol-4- t ***A, 1 Jyl)urea CK.^r" " WxhT! V-A H H j XX'' (S’)-l-(8-chlorochroman-4-yl)-3- (2-(3,3- f / O'""' Adifluoropyrrolidin- 1 -yl) thiazol-4-yl)urea? r\ / > a C! X Ji zZ'~‘N; X ''N' ' N p JHH L r 1 -((S)-8-chlorochroman-4-yl)-3- (2-((7?)- c3 -hydroxypyrrolidin- 1 - yi)thiazol-4- yl)ureal-((5r)-8-chlorochroman-4-yl)-3- 0""(2 -( (S) -3 -hydroxypyrrolidin- 1 -y 1) 9thiazoI-4-yl)urea Cl-XX, A 1 X-X "s r " N' " N" " N V-AH HAH1 -((S)-8-chlorochroman-4-yl)-3- (2-(3- c o -- shydroxy-3-(trifluoro raethyl)pyrrolidin- J. 1 J! 2-V '" / l-yl)thiazol-4- yl)urea CKV r " K 'N'“"( H H ■' \--'F X. Jn nHO XFF-80- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 3 \ p"~ Chemical Name Structure \ l-((S)-8-chlorochroman-4-yl)-3- (2-(3- hydroxy-3 -(trifluoro methy l)py rrolidin- Vi / ’1 -yl)thiazol-4- yl)urea CK 1 J, A 1 / -AII JH H, A KFF(S)- 1 -(8-chlorochroman-4-yl)-3- O'"'X0 / / '"' fO (2-( 1 -(oxetan-3-yl)-lH-pyrazol-4- yl)thiazol-4-yl)urea. AYVYif B K" 'N(5)- 1 -( 8 -chlorochroman-4-yl)-3 - (2-(3 - F fluoro-4-(methylsulfonyl) b / b-' O' '? rVz<? phenyl)thiazol-4-yl)urea Clx1 H H O (S)'- 1 -(2-(4-((2-aminoethyl)sulfonyl)phenyl)thiazol-4-yl)-3-(8- chlorochroman-4-yl)urea | \ H H °1 -((5) -8 -chlorochrom an-4-yl) -3 - NH (2-(l-(pyrrolidin-3-yl)-12 / - pyrazol-4- 0 r--S. A / yl)thiazol-4-yl)ureaCK 1 j. J J[ / . / '" T 'N "'hr " N \:5:=N1 J H Hl-((5)-8-chlorochroman-4-yl)-3-.. NH (2-(l-(pyrrolidin-3-yl)-U7pyrazol- o '' - O:■s.-b / 4-yl)thiazol-4-yl)urea 1CK II ii "hF "■zX H H(5)- 1 -(8-chlorochroman-4-yl)-3- 0 0 • S(2-( 1 -methyl- 1H- 1,2,3 -triazol-4- yl)thiazol-4-yI)urea Ck 'X.f ' j" Y 'If ’ N'(S)- 1 -(8-fluorochroman-4-yl)-3-(2- ( 1 -(tetrahydro-2H-pyran-4-yl)-lH- pyrazol-4-yl)thiazoi-4-yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 3 i 2 / \ * Chemical Name Structure K A (5)- 1 -(2-( 1 -ethyl- l / f-pyrazol-4- i / iz ^~- yl)thiazol-4-yl)-3-(8-flu 7 O r~~S ioro chroman-4- R 1 1 II 1 A XXyl)urea X i ®i ijt J ’X <-■* "x M” 'M' x \ 1 x H fl? Xc N'(S)-l-(8-chlorochroman-4-yl)-3- (2-(4- ((trifluoromethyl) xCKsul fonyl )phenyl )thiazol-4-yl )urea K4 ZT o Ozx zx\ / (S)- 1 -( 8-chlorochroman-4-yl)-3- d Z \ A \ X.(2-(4-((2-(m y { 0 \ 7 o.. 9 rA o.. / ethylammo)ethyl) CK,,o. X, J. A / A KJ / ■ b Y \ / sulfonyl)phenyl)thiazol-4-yl)urea / -y N " N 'NH! H M 0 ol-((5)-8-chlorodiroman-4-yl)-3- (2-( 1 -(tetrahydrofuran-3 -y 1)- IH- pyrazol-4-yl)thiazol-4-yl)ureaCl\l-((S)-8-chlorochroman-4-yl)-3- r”'°\ (2-( 1 -(tetrahydrofuran-3 -yl)- 1H- X t / 5 - pyrazol-4-yl)thiazoI-4-yl)ureaCK ' 'N' 'N \-^NJ H HV' T (S)-l-(8-chlorochroman-4-yl)-3- (2-(4- 0 r-Kmethylpi perazin- 1 -yl) th iazol -4-y l)ureaCk. A J., A JL N 6 •f X -*N" " K 'N \ ZN-■ [ J H Hl-((5)-8-chlorochroman-4-yl)-3- O" ' 0 'S, / "•“'■X (2-((J?)-3 -hydroxypiperidin- 1 - yl)thiazol- 4-yl)urea L i jl I )ZV hr' 'N' N X. / • H H \ > OH (5)-l-(8-chlorochroman-4-yl)-3- (2- (piperidin- 1 -yl)thiazol-4- yl)urea-82- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure(X)-l-(8-chlorochroman-4-yl)-3- (2- o^’A o fA / — \ morpholinothiazol-4-yl)ureaCK A A. A £ K < 'N' 'N' N \ _ / 1 J H H(S)-l-(8-chlorochroman-4-yl)-3- (2-(4- o <(dimethylphosphoryl) phenyl)thiazol-4- yl)urea CK.. N N x / ;. JHH ■ ’ (S)- 1 -(8-chlorochroman-4-yl)-3- (2-( 1 - 0" K o <r-'SxPA cyclopropyl- 1 JZ-imidazol -4- yl)thiazol- 4-yl)urea CK A Ji 1 A / Y T Y' YTXN" " N AKJ H HN(5)- 1 -(8-chlorochroman-4-yl )-3- (2-(5 - 9. ''i or-s0(methylsulfonyl)pyridin-2- yl)thiazol-4- CK. A J.. JI A J. J v J yl)urea '¥ Y ’" N' "hr ’N / v.1. JH H£ (5)- 1 -(8-chlorochroman-4-yl)-3- cA > 0 KA fcKY (2 -(2 -methyl -2H- 1,2,3 -triazol-4- I J 1 J / •■■■• ■< yl)thiazol-4-yl)urea Clx<■ 'AY N 'IMH J H H1 -((S)-8-chlorochroman-4-yl)-3- (2- 0 pH (2,2,2-trifluoro- 1 -hydroxy ethyl)thiazol- 4-yl)urea CK A >> A AA’V\ Y Y N' N' N J...n n \ K YFF1 -((S)-8-chlorochroman-4-yl)-3- (2- o'A o YS\ P (2,2,2-trifluoro- 1 -hydroxy ethyl )thiazol-H4-yl)urea CK A-,. A Y '■(i Y N N N y — pH HP h l-((5)-8-chlorochroman-4-yl)-3- (2-( 1 -(2-hydroxypropyl)- HI- pyrazol-4- CK i 1 t i r r yl)thiazol-4-yl)urea OH J H Hl-((5)-8-chlorochroman-4-yl)-3- o'A c(2-( 1 -(2-hydroxypropyl)- HI- pyrazol-4- CK 1 J- J J / -A r yl)thiazol-4-yl)urea • Y'"' YN OH JHHIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-((S)-8-fluorochroinati-4-yl)-3-(2- (3- o '*' > 0 1<--A hydroxypyrrolidin-l-yl) thiazol- 4-,.i 1. J V-V J yl)urea W " N" N ^--v.H H OH(S)- 1 -(8-chlorochroman-4-yl)-3- (2-(4-((2-(dimethylamino)ethyl)sulfonyl)phenyl)thiazol-4-yl)urea(S)-l-(8-chlorochroman-4-yl)-3- (2-(2- ( o rs, P hydroxypropan-2-yl) thiazol- 4-yl)ureaHnc / v. X' Jl JLr v ■'V r " N- N$ V 4q \ _ i H1 -(2-( 1 -amino-2,2,2- '■■'-j o ^^2 trifluoroethyl)thiazol-4-yl)-3-((7?)- 8- CixV 1o.. JI Jl >-<* chlorochroman-4-yl)ureaH H / V F FAl-((J?)-8-fluorochroman-4-yl)-3- (2-(3- O ' '' 0 s. js.., hydroxypyrrolidin- 1 -y 1) thiazol-4- yl)urea, L JL JL Z'A J W " NH H OH1 -(2-( 1 -aminoethyl)thiazol-4-yl)- 3 - c O r 'SNH-> (tft)-8-chlorochroman-4-yl)urea 1 i Fi \O... Jl JI / -r " ’V ' ’ hr 'NH H1 -(2-( 1 -aminoethyl)thiazol-4-yl)- 3 - c r O irA NH (tft)-8-chlorochroman-4-yl)urea j’l *! \ / '?Ch. II jj y- - C " N " N \ F H1 -((J?)-chroman-4-yl)-3 -(2-( 1 - hydroxyethyl)thiazol-4-yl)urea ofr"S\ OHxA A >v( w 'N \ H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 3 o.. S o OX== Chemical Name Structure M' ' X V / ' 1 -((J?)-8-fluorochroman-4-yl)-3- (2-( 1 - j iiO' 0 6-- hy r x e h l tsf. £ i d o y t y ) hiazol -4- yl)urea t Jt i OH i j I / N N 1 N \ n J M* H >4O C \—< o™l-((J?)-8-fluorochroman-4-yl)-3- (2-( 1 - > Z.. T ■( x Ohydroxyethyl)thiazol-4- yi)urea rA \ o rA PHF\. L X A-" T / \. N‘ " N' AKN / A \ j: L nl M nJ / \.1 -((;S,)-8-fluorochroman-4-yi)-3 -(2- ( 1 - O"'hydroxyethyl)thiazol-4-yl)ureaxKl-((5)-8-fluorochroman-4-yl)-3-(2- (1- JUULShydroxyethyl)thiazol-4-yl)urea 0'^\(S)-l-(8-chlorochroman-4-yl)-3- (4-(4- O '(cyclopropylsulfonyl) phenyl)thiazol-2- 1c3o „. O. A"'-1?'.._4,,, yl)urea ' N "'N'" " IM £_ / ' x / H H. 6 g (5)-l -(8-chlorochroman-4-yl)-3- (4-(4- C(ethylsulfonyl)phenyl) thiazol-2-yl)urea I JNH1 -((S)-8-chlorochroman-4-yl)-3- (4-(4- c b 9 / •— o (S-methylsulfonimidoyl) phenyl)thiazol- Cl-^ J 1 £ / — <2-yl)urea " y / ~f'“~H H HN1-((S)-8-chlorochroman-4-yl)-3- (4-(3- (S-methyl sulfonimidoyl)phenyl)thiazol- 2- yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3 V\z < / s Chemical Name StructureO 5 (5)- 1 -(8<hiorochroman-4-y 1 )-3 - (4-(5- c J (methylsulfonyl)pyridin-2- yl)thiazol-2-? kJ o.. z-- ifk'' ' yl)urea ci.....4, J t \'W'"' IH tHf "NN--Z r0 K CO— - l-((5)-8-chlorochroman-4-yl)-3- (4-(3 -(N, 1 -dimethyl- 1 -pheny 1 -?,6- sulfanediimine) thiazol-2-yl)urea O ' " ""CL,., Al-((5)-8-chlorochroman-4-yl)-3- (4-(3 -( 1 -oxido-4-oxo-3,4-dihy dro- 2H- 116,2, 5 -thiadi azol- 1 - yl)phenyl)thiazol-2-yl)urea Q’''(, S')-l-(S-chiorochroman-4-yl)-3- (2- c(isopropylamino)thiazol-4- yl)urea o r" Ac L 1 X A' \ H H / (5)-l -(8-chlorochroman-4-yl)-3- (2-( 1 - methyl- 12f-imidazol -4-yl) thiazol-4- 0- 7 0r-Ssyl)urea CK 1 1 A 1Y'k' 'N" " N' 'Nl JH H1 -((S)-ch rom an-4-yl)-3 -(2-(3 - hydroxypyrrolidin- 1 -yl)thiazol-4- 0' > o r A z'- yl)urea J J Jl * / -N 1x' N ' N V--\ J H H OH1 -((7?)-8-chlorochroman-4-yl)-3- (4-( 1 - hydroxyethyl)thiazol-2- yl)urea C 0 S-A 0H c1X-'" A X X wbT N \ J H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure1 -((J?)-8-chlorochroman-4-yl)-3- (4-( 1 - hydroxyethy l)thiazol -2- yl)urea O'""""-] 0 SY OH C!. 1 1 1 X WW 'N- y ji J H Hl-((7?)-8-chlorochroman-4-yl)-3- y-S OH (2-(cyclopropyl(hydroxy)? '^1 f ll Z-4 methyl)thiazol-4-yl)urea cY " N_[ J H F!> l-((7?)-8-chlorochroman-4-yl)-3- OO'(2-(cyclopropyl(hydroxy) '''I ( rA methyl)thia CK 'X < o / .zol-4-yl)urea / ’ \ / y1 / \ J 7..HHy(5)- 1 -(8-chlorochroman-4-yl)-3 - x9'""(2-(4-cyanophenyl)-5-methyl ''9 z o \-s —CKv1 J. JI »thiazol-4-yl)ureaXY‘ '" N"VN" N \.. / X H H><?- A Z.(5)- 1 -(8-chlorochroman-4-yl)-3 - (4-(4-cyanophenyl)-5-methylA f thiazol-2-yl)urea f (jr I ill 1 -((5)-8-chlorochroman-4-yl-4-<i)-rS O" A ( 3 Z 3 -(2-((7?)- 1 -hy droxy ethyl-2, 2,2- i -D 1! CK Y A* cA)thiazol-4-yl)Lirea" Y Y W Y'Y-D H$ D 1 -((5)-8-chlorochroman-4-yl-4-<i)- 0^ 0 r 'A;0H 3 -(2-((5)- 1 -hy droxy ethyl-2, 2,2- c. A > 1 A W < A)thiazol-4-yl)urea'if ~YNV-n b! H H / \DkY"DD (5)-l-(2-(acetyl-r / 3)thiazol-4-yl)-3- X 'l 0 r 'A o (8-chlorochroman-4-yl-4-<i)urea 1 A i il cf Y VVN-"' " N \ H H XY D bIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3 LL Chemical Name Structure / O, (5)- 1 -(8-chlorochroman-4-yl)-3 - Q' ''(2-vinylthiazol-4-yl)urea rs\Ck... l I / \ J. k" A H \ h(5)- 1 -(2-acetylthiazol-4-yl)-3 -(8- 0'"' s chlorochroman-4-yl)urea 1 9Cl\. / .-K. / H ( / \. k Jsy t - ' ■N'" ' N 1 p b \ — H H o(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-(3,3 -difluorocyclobutane- 1 -0carbonyl)thiazol-4-yl)urea Ck(5)- 1 -(2-(bicy clo [ 1.1.1 ]pentan- 1 - yl)thiazol-4-yl)-3-(8- 0 rA / . chlorochroman-4-yl)urea. I Jl’" N'' 'N' 'NH H1 -(2-(bicyclo[l.1.1 ]pentan- 1 - o ' o » --■" A pH yl(hydroxy)methyl)thiazol-4-yl)-3- X / ((5)-8-chlorochroman-4-yl)urea cu J-.,. -N J-L N 'N \ H H / 1 -(2-(bicyclo[l.1.1 ]pentan- 1 - \ OH yl(hydroxy)methyl)thiazol-4-yl)-3- o'" o r((5)- 1! II i" X _8-chlorochroman-4-yl)ureaI J(S)- 1 -(2-(bicyclo [1.1.1 ]pentane- 1 -H Hcarbonyl)thiazol-4-yl)-3-(8- chlorochroman-4-yl)urea C1\ l,1 1 1 >-< ' N' N \ H H / ' Y ■'■"kIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3- O'XX o rA pH (2-((3,3- difluorocyclobutyl)(hydroxy)meth Ckv, L J A 1VN'N yl)thiazol-4-yl)urea i H H / '■'>F l-((5)-8-chlorochroman-4-yl)-3- cXX o X, OH (2-((3,3- / \ * difluorocyclobutyl)(hydroxy)meth Ck. 1 1 11 J!,h-('' 'V A' 'N" " N * yl)thiazol-4-yl)urea ( O — H H / k Jf' k F(A) - 1 - (2 - ( 1 -acetylazeti din-3 - c> o •■ Ayl)thiazol-4-yl)-3-(8- chlorochroman-4-yl)urea CK 1 J.1 Ji. kA w z \ N hT 'N V Sk H / H 0 / l-(2-acetylthiazol-4-yl)-3-(8- chloro-4-methylchroman-4-yl)urea Xo / CKl-(2-acetylthiazol-4-yl)-3-(8- o o,-rA i zP chloro-4-methylchroman-4-yl)urea i # ’ j Cl. X Ji. X~“'Z ” N ' X' " N ' ' o H HO '1 -(2-acetylthiazol-4-yl)-3 - ((37?,47?)-8-chloro-3- methylchroman-4-yl)ureal-((5)-8-chlorochroman-4-yl)-3- n.--s OH (2-(l -hydroxy ethyl- 1,2,2,2- c / 4)thi azol -4-yl )urea? J 11 i > XDV n " X n * / X \IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure1 -(2-acetylthiazol-4-yl)-3 - ((25,45)-8-chloro-2- methylchroman-4-yl)urea 0 o rA.9C I Ji. / 9■" N 'IM \ H H1 -(2-acetylthiazol-4-yl)-3 - ((35,45)-8-chloro-3- methylchroman-4-yl)urea C 1,1 -(2-acetylthiazol-4-yl)-3 - ((27?,4S)-8-chloro-2- methylchroman-4-yl)urea o r'A P Cl.... \,. / J.1.?. -c ’N " N"' 'NH Hry' / 1 -(2-acetylthiazol-4-yl)-3 - ((35,47?)-8-chloro-3- cY r Q 4-Y A methylchroman-4-yl)urea c X 1,1A H H1 -(2-acetylthiazol-4-yl)-3 - ((37?,4S)-8-chloro-3- 0 " ■ " ■ ■ o -S, C methylchroman-4-yl)urea c 4'X.. J. 1" AT NH Hl-((5)-8-chlorochroman-4-yl)-3- -y' X OH (2-(l -hydroxy ethyl- 1,2,2,2- Y i ¥ / \ i. D c / 4)thi azol -4-yl )urea ck. X A. X X- AY Y” 'NV-n H H ADl-((5)-8-chlorochroman-4-yl)-3- cX'Y o rA? (2-(l -hydroxy ethyl- 1,2,2,2-Hni1ii ic / 4)thi azol -4-yl )urea ci., A A Jk # A' A Y N ' N N V H H / \D□ DIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3- (2-(2- (methoxymethyl)cyclopropyl)thiazol-4-yl)urea O'" ""'i o •sk Ck^ J. 1 JI >-40AT ''N" 'N HH Hl-((5)-8-chlorochroman-4-yl)-3- *... OH (2 - ( 1 - (3 -hy droxy cy clobutyl)- Ci' O r--5.UTpyrazol- b ii " 4-yl)thiazol-4-yl)urea 'N ' N N;NH H(5)-l-(2-(acetyl-t / 3)thiazol-4-yl)-3- / \ \o O — —? *•.(8-chlorochroman-4-yl)urea 9'" ''1 0 irA z. P / % \. JL,1 / ."'N" ' N' 'N V...nr H H / \DD D(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-( 1 -(3,3 -difluorocy clobutyl)- UTpyrazol- O'"'""'4-yl)thiazol-4-yl)urea Ck, ■... 1 1 >. / T" N 'N' 'N.z KH Hl jl-((5)-8-chlorochroman-4-yl)-3- O'"'A(2-(l -hydroxy ethyl-2, 2,2- O k- A PH< A)thiazol-4-yl)urea. I 1JyJ "'N"" 'N"" ''N Y H H ADD b l-((5)-8-chlorochroman-4-yl)-3- O''' \ o.r’s^ OH (2-(l -hydroxy ethyl-2, 2,2- < A)thiazol-4-yl)urea... 1 1’'N-' 'N-' 'N V. - H H / \D0 D l-((5)-8-chloro-6- O -s (trifluoromethoxy)chroman-4-yl)- si \, OH 3-(2-(l -hydroxy ethyl)thiazol-4- L n o A-Az x'yl)ureaH H4A-91- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-((5)-8-chloro-6- ( A 0 r'" S (trifluoromethoxy)chroman-4-yl)- / \ * PH 3-(2-(l -hydroxy ethyl)thiazol-4- Cl\ X, A i A-A yl)ureaJ H H□F'""'Fl-((5)-8-chlorochroman-4-yl)-3-.... OH (2-(2- i (hydroxymethyl)cyclopropyl)thiaz Q '"0,-S, X* ol-4-yl)ureaC;.. A, JL A'N' 'N" N HH Hl-((5)-8-chlorochroman-4-yl)-3- _,, OH (2-(2- (hydroxymethyl)cyclopropyl)thiaz C o A A* ol-4-yl)ureaOk X., L 1 1 A-A V?<' >r' 'N HH Hl-((5)-8-chlorochroman-4-yl)-3-... OH (2-(2- (hydroxymethyl)cyclopropyl)thiaz c Q;■ s A* ol-4-yl)ureaCk. 1 1 >--4A ' N ' 'K " N HH Hl-((5)-8-chlorochroman-4-yl)-3- _,, OH (2-(2- (hydroxymethyl)cyclopropyl)thiaz ( A OS / (* ol-4-yl)urea ok. J H i A-Aa >r "'N" 'N HH HA-(l-(4-(3-((5)-8-chlorochroman- 9 4-yl)ureido)thiazol-2- c A o rA HN A- ■ yl)ethyl)methanesulfonamideP"- A AX A ° ■ 'N N N \H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure / V-(l-(4-(3-((k)-8-chlorochroman- 9 4-yl)ureido)thiazol-2- Yyl)ethyl)methanesulfonamide 1 - V \ A > V 'N‘ N' 'N \ | H H(5)- 1 -(8-chlorochroman-4-yl)-3 -! - \ (2-(5,6-dihydro-4 / f-pyrrolo[l,2- '" A 0 x-s 1 / / ?]pyrazol-3-yl)thiazol-4-yl)urea o' H « V X 'N Ci... A.. x X A I Y 'N'' 'N \-^N H Ho(5)- 1 -(2-acetylthiazol-4-yl)-3 -(8- " H " H T~ / / \ A' 0.:--S chloro-6- C(trifluoromethoxy)chroman-4- I x Ji yl)urea >r'"' ^Nz\| H HcXrF2-(4-(3-((5)-8-chlorochroman-4- osyl)ureido)thiazol-2- o >' OH yl)cyclopropane-l -carboxylic acid 9 ■' > o r \ Xi iiX " V ''!< 'NH Hl-((5)-8-chlorochroman-4-yl)-3- o > o(2-( 1 -hydroxy ethyl- 1 -c / )thiazol-4- 1 II A - D yl)urea CK X Y, JL JL / A V ¥ Y " Nif H Hl-((5)-8-chlorochroman-4-yl)-3- (2-( 1 -hydroxy ethyl- 1 -c / )thiazol-4-? « [i kX yl)urea Ck Xx.••X A * \ A T ’ZN" YT 'Nxyh hIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure(5)- 1 -(2-acetylthiazol-4-yl)-3 -(8- o "chloro-6-methoxychroman-4- A? rs\, P yl)urea Civ. 'v. X. r "f r N' ’’N" " NH Hl-((5)-8-chloro-6- ox" O r — S methoxy chroman-4-yl)-3 -(2-( 1 - Y o \ * CH hydroxyethyl)thiazol-4-yl)urea Ck.vW 'fA \ H H....6l-((5)-8-chloro-6- \0 0 • — s methoxy chroman-4-yl)-3 -(2-( 1 - ¥ \ * OH hydroxyethyl)thiazol-4-yl)urea Cl..... A■; '■■A AT ^o " bT \ H Hx6(R)- 1 -(2-acetylthiazol-4-yl)-3 -(8- ochlorochroman-4-yl)ureax9 rA o Gk... 9 O A L 1. 4N ' ''N \ H H5(5)-4-(3-(8-chlorochroman-4- O'yl)ureido)thiazole-2-carboxylicxo A acid.. JI jl"" N' NnHO n n Li ’methyl (5)-4-(3-(8-chlorochroman- o '"4-yl)ureido)thiazole-2-carboxylateCh., J\AJIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3- (A A o A pH (2-(l,2-dihydroxyethyl)thiazol-4- i P — / yl)urea Cl-,„ >■-. A.-A >■ / *x H H " OH(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-(6-oxo- 1,6-dihy dropyri din-3 - yl)thiazol-4-yl)ureal-((5)-8-chlorochroman-4-yl)-3- \= / o A OH (2-(l,2-dihydroxyethyl)thiazol-4- j. | II h X-.... / yl)urea CI\ / y _$ \ \ T _ -N N N \^H] H HW(5)- 1 -(8-chlorochroman-4-yl)-3 -nS OH (2-(3 -hydroxy oxetan-3 -yl)thiazol- X^^ / I ft \ / 4-yl)urea A AA ' A'' A | / H H ~O A(5)- 1 -(2-(azeti din-3 -yl)thiazol-4- O' > O;r'A J J yl)-3-(8-chlorochroman-4-yl)urea 1 1! i ■ \ / X 1 X, A A NH V pp N' 'N oH HY- 4 (5)- 1 -(8-chlorochroman-4-yl)-3 - CA rt S 1* (2-(3-fluorooxetan-3-yl)thiazol-4- V o \ / fiyl)urea P —A x‘A; A"’ A N! 1 H H 0(5)- 1 -(8-chlorochroman-4-yl)-3 - O’XG P',(2-(oxetan-3-yl)thiazol-4-yl)ureaCh-. 1 1 >-A 'A' A' 'N V H H1 -(8-chloro-4-methylchroman-4- ox' O OH yl)-3-(2-(l -hydroxy ethyl)thiazol- 4-yl)urea CK x^ A A A PA 'N' 'N \ H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-(8-chloro-4-methylchroman-4-yl)-3- o" ' " A afr"\ OH (2-(l -hydroxy ethyl)thiazol-4-yl)urea Il t Xv, L... A, \ A"' " A \ H Hl-(8-chloro-4-methylchroman-4-yl)-3- Cf'(2-(l -hydroxy ethyl)thiazol-4-yl)urea? r\ XH Hrl-(8-chloro-4-methylchroman-4-yl)-3- 7” / _ 0--'(2-(l -hydroxy ethyl)thiazol-4-yl)urea o f'-y&pHCI\ / \ AU.. A 1 H 'A' A' A \ / \ X H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - " X" o r'A(2-(l -hydroxy ethyl)thiazol-4-yl)urea OH CK A I A Ji AY r'' 'N' " N \ H H IJ1 -(8-chloro-3 -methylchroman-4-yl)-3 - 0 A"'S* pH (2-(l -hydroxy ethyl)thiazol-4-yl)ureaCK " Sy 1 " N" '■’N" " N \ H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - (2-(l -hydroxy ethyl)thiazol-4-yl)urea 1 * O fA’S\ *C1- 1 1 AY \ry ■'N" " N" 'NH H1 -(8-chloro-3 -methylchroman-4-yl)-3 - O r;^- OH (2-(l -hydroxy ethyl)thiazol-4-yl)urea T x X Jl XX"A' A" N x H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - £(2-(l -hydroxy ethyl)thiazol-4-yl)urea 0 A A * PH. 1 1 > A '-fT ' A-" ' A \ H H-96- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure1 -(8-chloro-3 -methylchroman-4-yl)-3 - o'' $ o «ZOH (2-(l -hydroxy ethyl)thiazol-4-yl)ureaCI\H H1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - methoxyethyl)thiazol-4-yl)urea cA "k o rA « P —CC.. i 1 IL JL' ' A ' P" N \! H H(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- o"'(methylthio)thiazol-4-yl)urea X o / r"s\ / J.1. JA A'"" " A "'N j H H1 -((4S)-8-chl oro-3 -methylchroman-4- P O <7 OH yl)-3-(2-(l -hydroxy ethyl)thiazol-4- *yl)urea Ck. X, I JL / k PP P" N \ H Hl-((4S)-8-chl oro-3 -methylchroman-4- ck O srA OH yl)-3-(2-(l -hydroxy ethyl)thiazol-4- yl)urea CL... JI JPA 'A * \ H Hl-((R)-8-chlorochroman-4-yl)-3-(2- (A A O r S(1 -hydroxy ethyl)thiazol-4-yl)urea i V II \ Oil Clx. X.r N 'hr N *\ H Hvl-((R)-8-chlorochroman-4-yl)-3-(2- O'' P Or— S(1 -hydroxy ethyl)thiazol-4-yl)urea i si \ OH CL..z.. X... A PcC N 'N' " N ' \ H HVIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structurel-((4S)-8-chloro-2-methylchroman-4- yl)-3 -(2-( 1 -hydroxy ethyl)thiazol-4- yl)urea 0 r; -'Ss. OH ■A'x A * \ < 'N'" " N \H Hl-((4S)-8-chloro-2-methylchroman-4- yl)-3 -(2-( 1 -hydroxy ethyl)thiazol-4- yl)urea o r"sx. OH I | |j Hz>_ / Cl\r< 'N" 'N \ I H Hl-((4S)-8-chloro-2-methylchroman-4- yl)-3-(2-(l -hydroxy ethyl)thiazol-4- yl)ureaO'<\s 0 OH1 J.. 11 1f 'V N' 'N \H Hl-((4S)-8-chloro-2-methylchroman-4- yl)-3-(2-(l -hydroxy ethyl)thiazol-4- yl)urea0OH A k 1. k kk k V N -N \H H(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- O' > 0 0 — (methoxymethyl)thiazol-4-yl)ureaX,1 1 J. A--7A"' y N|| H H2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- methylcyclopropane- 1 -carboxamideCK 1 J, It 1"vf ' ii" Y r 'N rfIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure2-(4-(3-((S)-8-chlorochroman-4-.i yl)ureido)thiazol-2-yl)-N-(P... PH methylcyclopropane- 1 -carboxamide T cCK. 1 1 1'V '"]< " NT N H i H H2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- T yl)cy clopropane- 1 -carboxamide ox1.,1 1 Ap - 'N P N j;H H1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - 0" > 0 rA pH hydroxy-2-methylpropyl)thiazol-4- I \ / . I i if A A yl)urea CK A A. - 'A \ p "p N N NI 1 H H / 1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - hydroxy-2-methylpropyl)thiazol-4- (A'A o A\ * <0HKyl)urea a..,1 A 1 J. PP X " W ■'N' 'N" ‘N ) _ | I H H ' 2-(4-(3-((S)-8-chlorochroman-4- \ yl)ureido)thiazol-2-yl)-N- 7 • -,. methylcyclopropane- 1 -carboxamide(Cis.,.2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- methylcyclopropane- 1 -carboxamide( P ofr —> S\ * i II V * / \ CK A A A P A A 'N HH HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- methylcyclopropane- 1 -carboxamide2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- yl)cy clopropane- 1 -carboxamide 0 o r-A J.* cr.. I 1 A / / " IN?' '■? H<'Nn / \ / _(S)- 1 -(8-chlorochroman-4-yl)-3 -(2-(5 - N y ( - o'" " X \ / o r"ssmethyl- 1 -(oxetan-3 -yl)- 1 H-pyrazol-4- \ 7 _J... J, \ JI Ji XX z yl)thiazol-4-yl)urea ■' " V';R _'” \ ■ R A...-Ni H \ H / \ > / A ' u 2-(4-(3-((S)-8-chlorochroman-4- Z Z\ yl)ureido)thiazol-2-yl)-N- A. ZH methylcyclopropane- 1 -carboxamide / nO'XT A o r >■“Z 1 1 A AA. k •- 1, AH " V H 'NH' IA w I * \ Z - 1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - (hydroxypropyl)thiazol-4-yl)urea R o rA? B -X x X N" X xx j H H 'N / \ / 1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - hydroxypropyl)thiazol-4-yl)ureaCRAc(S)- 1 -(8-chlorochroman-4-yl)-3 -(2-(3 - / ■' -o methyl- 1 -(oxetan-3 -yl)- 1 H-pyrazol-4- yl)thiazol-4-yl)urea fq,. A J.,. It J!.' ''"if " R11^ JH H / IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure(S)- 1 -(2-(4-(2-aminopropan-2- 0" O \ yl)phenyl)thiazol-4-yl)-3-(8- Ch 4 I 1 I4- chlorochroman-4-yl)urea XX 'Ar' " N v X X ii i H HN-(l-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- ( )r-~S HN-- / yl) j < \ * / \\ ethyl)acetamide—7— '" A"' x. N',-■< N y \ o H HN-(l-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- ( y"’ 4f) HN-~4 yl)ethyl)acetamide cc.„ L X, J" V A N N11 H(S)- 1 -(8-chlorochroman-4-yl)-3 -(2-( 1 - ( o'' 4 J rr'4methyl-3 -(trifluoromethyl)- 1 H- pyrazol-4-yl)thiazol-4-yl)urea(:|v. I., 'N. X N z-xi H H / Ok F-4F > (S)-l-(2-(2H- 1,2,3 -tri azol -4- o- 4 ) C""S\ Ns,. yl)thiazol-4-yl)-3-(8-chlorochroman- 4-yl)urea Ck,1. A- IL. 1 W T "4 V AT 'N'- 'NHH L JH(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- ( 1,3 -dimethyl- 1 H-pyrazol-4-? r V / v yl)thiazol-4-yl)urea n 1 1 JI A Z \;Y N N ’ X j | H H / (S)-4-(3-(8-chlorochroman-4- yl)ureido)thiazole-2-carboxamide O'"' 40dj 1 y f 44 CK lx. A'Y, * \ v yNNH, | || H H2(R)- 1 -(4-(3 -((S)-chroman-4- yl)ureido)thiazol-2-yl)pyrrolidine-2- '1 V r \ 4'4 carboxamide X 1 '-.N■••••■ A -NV-k H H / O'"~\NILIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name Structure1 -(2-(l -aminoethyl)thiazol-4-yl)-3 - (((S)-8-chlorochroman-4-yl)urea o rA NIT.Cl\ i i xx ~H H1 -(2-(l -aminoethyl)thiazol-4-yl)- O'"' O NI:h 3-((S)-8-chlorochroman-4-yl)ureaCK.... 1 1 Y '" Y Y 'N \ H H(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-(l-methyl-l / f-l,2,3-triazol-5- Z o r A A yl)thiazol-4-yl)ureaOk. X 1 A A AA T Y Y' Y Y N V--N | 1 H H(5)-4-(3-(8-chlorochroman-4- yl)ureido)- / V-methylthiazole-2- 0 " 'i? r\Y carboxamide!. M. A, kCK YK Y AA AZ " Nr r H H / N-((R)- 1 -(4-(3-((5)-chroman-4- o 1 O rZ yl)ureido)thiazol-2-yl)pyrrolidin- J 1 Ji! o 3 -yl)methanesulfonamide J Y-' 'Y Y v-Y* * J H H NYH 5 (5)-l-(2-(2-oxa-6- azaspiro [3.3 ]heptan-6-yl)thiazol-4- o""'X o rA / x y 1 ) - 3 -(chroman-4-yl)urea X J-, 1 X- x x H H HN-((R)- 1 -(4-(3 -((5)-chroman-4- O'"' "yl)ureido)thiazol-2-yl)pyrrolidin- I..., JL JL. YY j o 3-yl)acetamide Y 'N V--V ff IQ H HH(5)- 1 -(8-chlorochroman-4-yl)-3 - O ' A 0 kA / (2-((2- methoxyethyl)(methyl)amino)thiaz 1 1 JLY'"' " N " N V ol-4-yl)urea H H \Y,, J P-102- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 3Chemical Name StructureA-((A')- 1 -(4-(3-((A')-chroman-4- O'"' O <■.'.Sx Z'-'. yl)ureido)thiazol-2-yl)pyrrolidin- A ).1 A AV i3 -yl)methanesulfonamide0" V AT 'N' 'N V—H0 ' N-((S)- 1 -(4-(3 -((S)-chroman-4- yl)ureido)thiazol-2-yl)pyrrolidin- ■? r\ / ■>3-yl)acetamide ■ A '■>.. / "'A A N A N # “K 1 / / 0 i H H s-, A H1 -((R)-chroman-4-yl)-3 -(2-(l - hydroxyethyl)thiazol-4-yl)urea o '' 0 r"s, 0H X X, A AJ i: H H10134] In another aspect, provided herein is a method of treating PMD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by formula (IV):Formula (IV)or a pharmaceutically acceptable salt thereof, wherein:A is thiazole, 2-pyridyl, pyrazole, oxazole, azaindole, substituted thiazole, substituted 2 -pyridyl, substituted pyrazole, substituted oxazole, or substituted azaindole;Ri is hydrogen, halogen, Ci-Ce alkyl, substituted Ci-Ce alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclyl, or substituted heterocyclyl;-103- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOwherein A is connected to N via a C-N bond; and* denotes a chiral carbon.

[0135] In some embodiments, the compound of formula (IV) is a compound listed in Table 4.Table 4Chemical Name Structurel-[2-(2-pyridyl)thiazol-4-yl]-3-[rac- (4S)-8-(difluoromethyl)-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea x'r A ' LAl-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[l-[rac- ""'X.(lR,3R)-3- A hydroxycyclopentyl]pyrazol-3 - JvA yl]ureal-[rac-(4S)-8-chloro-3,4-dihydro-2H- j A\pyrano[3,2-b]pyridin-4-yl]-3-[l-[rac- (lS,3S)-3- 1 1..., hydroxycyclopentyl]pyrazol-3 - yl]urea i J "01 -[2-( 1 -methyl-6-oxo-3 - pyridyl)thiazol-4-yl] -3 - [rac-(4 S) -8 - ' 1 J A \ _ / chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]urea T V$ r~'\1 - [2-(3 -methyl- 1,2,4-thiadiazol-5 - j AA TA A-x A \ -7 yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- Xy' 'Nj A* 'A. A A' \.3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea x.x, Al-[2-(6-oxo-lH-pyridin-3-yl)thiazol- 4-yl]-3-[rac-(4S)-8-(difluoromethyl)- A A A A3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea A " "N-methyl-6-[[rac-(4S)-8- F(difluoromethyl)-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyridine-2-carboxamide AT 6-104- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4 V. X'-'' ' Chemical Name Structure 1 A$>1 / / A I1 - [ 1 -(2-pyridyl)pyrazol -3 -yl] -3 - [rac- ■X A / (4S)-8-(difluoromethyl)-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea X, Z U—r' * / r"\L Jl-[2-(2-methyltetrazol-5-yl)thiazol-4- -x J yl]-3-[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] ureal-[(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 - [2 -(6 - Hoxo- lH-pyridin-2-yl)thiazol-4- yl]ureamethyl 3-[4-[[rac-(4S)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4- <3yl]carbamoylamino]thiazol-2- Byl]bicyclo [1.1.1 ]pentane- 1 - carboxylatel-[(4S)-8-chloro-3,4-dihydro-2H- C4vL X. >-A V<, pyrano[3,2-b]pyridin-4-yl] -3 -[ 1 -(6- BB— ^7 oxo- lH-pyridazin-3 -yl)pyrazol-3 - yl]ureal-[2-(4-methyloxazol-2-yl)thiazol-4- yl]-3-[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea1. J x 1 H1 -( 1 -pyridazin-3 -ylpyrazol-3 -y 1) -3 - B 4-4 - - [rac-(4S)-8-chloro-3,4-dihydro-2H- Ipyrano[3,2-b]pyridin-4-yl]ureaS; £v A A V. L / / —X X. X Ax,1 - [ 1 -(4-pyridyl)pyrazol -3 -yl] -3 - [rac- X 'X (4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structurel-[2-(5-fluoro-2-pyridyl)thiazol-4- - £ -y1 -g' J l XX v yl]-3-[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] ureav'"'A.. A. Z~A > l-[(4S)-8-chloro-3,4-dihydro-2H- ’V >4 \ pyrano[3,2-b]pyridin-4-yl] -3 - [2 -(6 - 0 / methoxy-2-pyridyl)thiazol-4-yl]urea / l-[(4S)-8-methyl-3,4-dihydro-2H- k A <YAAZ pyrano[3,2-b]pyridin-4-yl] -3 -[2-( 1 - methylpyrazol-3-yl)thiazol-4-yl]ureai 8 rV-Z^x 1 - [ 1 -(3 -pyridyl)pyrazol -3 -yl] -3 - [rac- j.; (4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]ureaS--\ XJ 1 - [2- [ 1 -(oxetan-3 -yl)pyrazol-3 - A / “■ / T yl]thiazol-4-yl]-3-[rac-(4S)-8-chloro- 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea•C' \ 1 - [2- [ 1 -(oxetan-3 -yl)pyrazol-3 - yl]thiazol-4-yl]-3-[rac-(4R)-8-chloro- •k: 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea1 rXz'Z x, / x / x Z \ i 1 -[2-( 1 -methyltriazol-4-yl)thiazol-4- rV yl]-3-[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structure1 -[2-( 1,5 -dimethylpyrazol-3 - i r / x^''K / A 1 yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- il "■N- 'N y _ •>; 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea< / 1 -[ 1 -(4-cyano-3 -fluoro- phenyl)pyrazol-3 -yl] -3 - [rac-(4 S) -8 - chloro-3,4-dihydro-2H-pyrano[3,2- X:-1 *■!b]pyridin-4-yl]urea7.7 ’. I X\ / x 1 -[ 1 -(2-oxo- lH-pyridin-4-yl)pyrazol- ■K. \i3 -yl] -3 -[rac-(4S)-8-chloro-3,4- dihydro-2H-pyran '■'X / X. \ \ ^-*7^ X ■■ o[3,2-b]pyridin-4- / \ _yl]urea1 -[ 1 -(6-oxo- lH-pyridin-3 -yl)pyrazol- / 3 -yl] -3 -[rac-(4S)-8-chloro-3,4- Si.w dihydro-2H-pyrano[3,2-b]pyridin-4- yl]urea X; J Xl-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[l-[rac- i I *(lS,3R)-3- k / hydroxycyclopentyl]pyrazol-3 -v'\ \C’H yl]ureaJ. I X 1 -( 1 -phenylpyrazol-3 -y 1) -3 -[rac-(4S)- r' 18-(difluoromethyl)-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]ureaO (TX / ; HJX A / f^~~i l-[(4S)-8-chloro-3,4-dihydro-2H- H ‘ - 4 pyrano[3,2-b]pyridin-4-yl] -3 - [2 -(3 - hydroxyoxetan-3-yl)thiazol-4-yl]ureaA1 -[2-( 1 -cyclopropylpyrazol-3- L yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea-107- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure1 - [2-(5 -methyl- 1,3,4-thiadiazol-2- yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- I I f '""ti ‘C \ F 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea1 2l-[2-(6-oxo-lH-pyridin-3-yl)thiazol- i y 8 \ Ax A X4-yl]-3-[rac-(4S)-8-chloro-3,4- / dihydro-2H-pyrano[3,2-b]pyridin-4- yl]urea« P'"\ > l-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[l-[2- -x V Aj;[rac-( 1 R)-2,2,2-trifluoro- 1 -hydroxyethyl] -4-pyridyl]pyrazol-3-yl]ureax / l-[rac-(4S)-8-chloro-3,4-dihydro-2H- A r \?• pyrano[3,2-b]pyridin-4-yl]-3-[l-[2- [rac-( 1 S)-2,2,2-trifluoro- 1 -hydroxyethyl] -4-pyridyl]pyrazol-3-yl]urea1 -[ 1 -(6-methoxy-3-pyridyl)pyrazol- 3-yl]-3-[rac-(4S)-8-chloro-3,4- i 1 £>-rVy dihydro-2H-pyrano[3,2-b]pyridin-4- Byl]ureax,, / 1 -[ 1 -(2-methoxy-4-pyridyl)pyrazol- I M - / / 3-yl]-3-[rac-(4S)-8-chloro-3,4- 5dihydro-2H-pyrano[3,2-b]pyridin-4- yl]urea0*'^" " N O J3H l-[rac-(4S)-8-chloro-3,4-dihydro-2H- 1 J... 1pyrano[3,2-b]pyridin-4-yl]-3-[4-[rac- AH( 1 S)- 1 -hydroxyethyl]oxazol-2-yl]urea-108- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structurel-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[4-[rac- X A Ah ’ ( 1 R)- 1 -hydroxyethyl]oxa 1 1 4zol-2- yl]urea '1Ci x1 -[ 1 -(4-cyano-2-fluoro- r ywy phenyl)pyrazol-3 -yl] -3 - [rac-(4 S) -8 - chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]ureal-[2-(3-methyl-lH-pyrazol-5- 1 Jyl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- vzl f 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea “'I'Jl-[2-(lH-pyrazol-3-yl)thiazol-4-yl]- X X A JA XX I 3-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]ureaN <?1 -[2-( 1 -methyl- 1,2,4-triazol-3 - X A / A 1 yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- XsX3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea ^,11 - [2 -( 3 -pyridyl)thiazol-4-yl] -3 -[rac- X- XX L £ AX (4S)-8-chloro-3,4-dihydro-2H- 1pyrano[3,2-b]pyridin-4-yl]urea<xl-[2-(4-pyridyl)thiazol-4-yl]-3-[rac- ■?r'?iA (4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]urea 3l-[2-[l-(2,2-difluoroethyl)pyrazol-3- yl]thiazol-4-yl]-3-[rac-(4S)-8-chloro- 3,4-dihydro-2H-pyrano [3,2- Z" X J b]pyridin-4-yl]urea£IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name StructureA, X A1 -[2-( 1 -methylpyrazol-3-yl)thiazol-4- yl]-3-[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] ureal-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[2-[l- '”''N r (2,2,2-trifluoroethyl)pyrazol-3- yl]thiazol-4-yl]urea Il-[rac-(4S)-8-chloro-3,4-dihydro-2H- is r"\ 2’^. xk... pyrano[3,2-b]pyridin-4-yl]-3-[2-[l- x;7:-' J. 1 '■■■x i --« 11(trideuteriomethyl)pyrazo [ >3 H!l-3 - yl]thiazol-4-yl]urea(S)- 1 -(2-(bicyclo[ 1.1. l]pentan- 1 - yl)thiazol-4-yl)- 3 -(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea L 1l-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 -thiazol- 4-yl-ureaArM Hu1 -[2-( 1 -methylpyrazol-3 -yl)thiazol-4- yl]-3-[rac-(4S)-8-(l-methylpyrazol-3- y 1) -3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea 4J1.1 1 A A A A T I J " *(S)-l-(8-ethyl-3,4-dihydro-2H- pyrano[3,2-: X A b]pyridin-4-yl)-3 -( 1 -phenyl- 1H- pyrazol-3-yl)urea 8 k A A / ! / O 'IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(S)-l-(8-cyclopropyl-3,4-dihydro- 2H-pyrano[3,2- b]pyridin-4-yl)-3-(l-phenyl-lH- A,pyrazol-3-yl)urea A A A A / A / P J J Btert-butyl (2-(3-hydroxyoxetan-3- yl)thiazol-4- fl \ / yl)carbamate CK i A A / — An A'"' [(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- j f A - / A b]pyridin-4-yl)-3 -(2-( 1 -ethyl- 1H- " \ \ " A A ATpyrazol-3-yl)thiazol-4-yl * A)urea / x1-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- (Ab]pyridin-4-yl)-3 -(2-((R)- 1 -hydroxy- 2-methylpropyl)thiazol-4-yl)urea A X A'', A '‘A AY \1 / 1-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-((S)- 1 -hydroxy- / <f» A A A A 1 A** / H X 2-methylpropyl)thiazol-4-yl)urea s.f1 X:(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -isopropyl- 1H- j r"\pyrazol-3-yl)thiazol-4-yl)urea7vzk A / A J(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- 1. Jb]pyridin-4-yl)-3-(2-(2-neopentyl- 2H- 1,2,3 -triazol-4-yl)thiazol-4-yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(4-cyanopyridin- || I / A 2-yl)- lH-pyrazol-3 -yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- •> jr""\.. X, / A b]pyridin-4-yl)-3-(2-(2-(tert-pentyl)- 0 ||,z> — / ? i 2H- 1,2,3 -triazol-4-yl)thiazol-4- i 8 8yl)urea 8l-((S)-8-chloro-3,4-dihydro-2H- % / \pyrano[3,2- / b]pyridin-4-yl)-3 -( 1 -(3 -fluoro-4-((S)- 2,2,2-trifluoro-l- A "‘hydroxyethyl)phenyl) - 1 H-pyrazol-3 - / yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(l-(3-fluoro-4-((R)- j J j L. / --< y~ / 2,2,2-trifluoro-l- hydroxyethyl)phenyl) - 1 H-pyrazol-3 - ’ ” ~ / V yl)urea k A(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- '"'i HCiZr\A.. i r- b]pyridin-4-yl)-3 -(2-(2-(2,2,2-:-S Htrifluoroethyl)-2H- 1,2,3 -triazol-4- yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- O'b]pyridin-4-yl)-3-(2- C: JLcyclobutylthiazol-4-yl)urea A. > l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(6-((S)-2,2,2- Ax, Ax trifluoro- 1 -hydroxyethyl)pyridin-2- Xi'' X'’ ‘'v'' yl)urea<1| '''I'£-112- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structurel-((S)-8-chloro-3.4-dihydro-2H- pyranoL3,2- b]pyridin-4-yl)-3-(6-((R)-2,2,2- £ A.',-'1' '■>>. / ■ A £ ''■x'1'' trifluoro- 1 -hydroxyethyl)pyridin-2-. yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(6-cyanopyridin- x " Sf X A JL- - 3 -yl)- lH-pyrazol-3 -yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- V.b]pyridin-4-yl)-3-(2-isobutylthiazol- W \4-yl)urea V 1 1 ‘"’X 1 1\ X?7(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -isopropyl- 1H- pyrazol-4-yl)thiazol-4-yl)urea X(S)-l-(l-(4-(3 -aminooxetan-3 - yl)phenyl)- IHpyrazol- 3 -yl)-3 -(8-chloro-3,4-dihydro-2H- 1 A. 1s!~~~ rASj pyrano[3,2-b]pyridin-4-yl)urea(R)-l-(l-(4-(3 -aminooxetan-3 - yl)phenyl)- IHpyrazol- 3 -yl)-3 -(8-chloro-3,4-dihydro-2H- X. JL Ji. X-S ~ <£. -i — pyrano[3,2-b]pyridin-4-yl)ureal-((S)-8-chloro-3,4-dihydro-2H-!•&.:pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(2-(2,2,2- / £ "'■£ / '" trifluoro- 1 -hydroxyethyl)pyridin-4- r 4 a r\_r£vyl)- lH-pyrazol-3 -yl)urea A J JIIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structurel-((S)-8-chloro-3.4-dihydro-2H- pyrano[3,2- „ >-4 b]pyridin-4-yl)-3 -( 1 -(4-fluoro-3 -((R)- 1 \ - z’ X 2,2,2-trifluoro-l-. \shydroxyethyl)phenyl) - 1 H-pyrazol-3 -KV. Y yl)urea Il-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(l-(4-fluoro-3-((R)- 2,2,2-trifluoro-l- jhydroxyethyl)phenyl) - 1 H-pyrazol-3 - yl)urea ((S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- n r \. / b]pyridin-4-yl)-3 -( 1 -(3 - z-A ASfe. / \\ A methylpyridin-2-yl) - 1 H-pyrazol-3 - XX - - - yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- < J., — < y..... b]pyridin-4-yl)-3 -( 1 -(5 -cyanopyridin- 8' ” - ' / 2-yl)-lH-pyrazol-3-yl)urea 1 v1(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- r X jj r v / b]pyridin-4-yl)-3-(2-isopropylthiazol- A J, JL JL 1 4-yl)urea < -Y HN\l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- 1I A, / W* b]pyridin-4-yl)-3 -( 1 -(4-((R)- 1 - T \ hydroxy ethyl)phenyl) - 1 H-pyrazol-3 - yl)urea 'xl-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( l-(4-((S)-l- hydroxyethyl)phenyl) - 1 H-pyrazol-3 - yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(( 1 r,3 S)-3 - hydroxy cyclobutyl)- lH-pyrazol-4- JzX J... A'-’ A A / — \ i yl)thiazol-4-yl)urea-114- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(S)-4-(4-(3-(8-chloro-3,4-dihydro- 2Hpyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2- -'A A 'Niyl - - i to \ ) N methylbenzamide to—A Vf it!(S)-l-(8-chloro-3,4-dihydro-2H- t 0 S -■ A'*” \pyrano[3,2- 1! 11 \ / '*■ J- A / JJI. / ~A\ / A-^ b]pyridin-4-yl)-3 -(2-(4- to cyanophenyl)thiazol-4-yl)urea / (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- / \ \ / b]pyridin-4-yl)-3 -( 1 -(4-cyano-2- / . \methylphenyl) - 1 H-pyrazol-3 -yl)urea & \.IA > \ / _l-((S)-8-chloro-3,4-dihydro-2H- 'A 0 ANpyrano[3,2- xA. A. / -A. / / ^- — ( b]pyridin-4-yl)-3 -( 1 -(6-((R)-2,2,2- ■ H / A » V - - \ trifluoro- 1 -hydroxyethyl)pyridin-3 - yl)- lH-pyrazol-3 -yl)urea “ A • fl-((S)-8-chloro-3,4-dihydro-2H- X i! A)pyrano[3,2- I::! > - Z \ / xA Ax- / -A A A r A"—<’ b]pyridin-4-yl)-3-(l-(6-((S)-2,2,2- a A " AZ A j \ trifluoro- 1 -hydroxy ethyl)pyridin-3 - z to / X yl)- lH-pyrazol-3 -yl)urea i s 1 1! l-((S)-8-chloro-3,4-dihydro-2H- i H pyrano[3,2- j 'b]pyridin-4-yl)-3 -( 1 -(6-((S)-2,2,2- trifluoro- 1 -hydroxyethyl)pyridin-3 - AKyl)- lH-pyrazol-3 -yl)urea Al-((S)-8-chloro-3,4-dihydro-2H- HO pyrano[3,2- b]pyridin-4-yl)-3-(l-(3-((R)-2,2,2- i - trifluoro- 1 -hydroxyethyl)phenyl)- 1H- >. A A \Ti A' A A / pyrazol-3-yl)urea*f!(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(5 - f A i r\ XT methylisoxazol-4-yl)thiazol-4-yl)urea A A A / MA i! 4:A / AIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- / A. P b]pyridin-4-yl)-3-(2-(2-(methyl-d3)- 2H- 1,2,3 -triazol-4-yl)thiazol-4-a, 1 1 A A. z~ A 7 yl)urea n I!i*A*(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- £ / : KaK\ o —A A A, A / '-A >-- / b]pyridin-4-yl)-3 -( 1 -(4- tj(methoxymethyl)phenyl)- 1H- jpyrazol-3-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 '-methyl- 1 'H- 1 / / ' 1 1 £ M Z; s;s- W '-'siX. >’ / 1 H!<[ 1,4'-bipyrazol] -3 -yl)ureal-((S)-8-chloro-3,4-dihydro-2H- Xpyrano[3,2- Il f b]pyridin-4-yl)-3-(2-(4-((R)-2,2,2- A A / ( >■-- / trifluoro-1- | ■ f'A. / \ hydroxyethyl)phenyl)thiazol-4- yl)ureaAl-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- j f Y 'AxA / x T b]pyridin-4-yl)-3-(2-(4-((S)-2,2,2- \ _ / x trifluoro-1- j| / V. hydroxyethyl)phenyl)thiazol-4- ] yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(4-(2- hydroxyethyl)phenyl) - 1 H-pyrazol-3 - yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- / pyrano[3,2- 0b]pyridin-4-yl)-3 -(2-(2-(3,3 - £ « Ax difluorocyclobutyl) -2H- 1,2,3 -triazol- k A T4-yl)thiazol-4-yl)urea ■k <•>(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- S j--.. b]pyridin-4-yl)-3 -( 1 '-methyl- 1 'H- A 1 II A 1 s A •< / \ I [ 1,4'-bipyrazol] -3 -yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(S)-l-(l -(3 -bromophenyl) - 1 H- pyrazol-3-yl)-3-(8- chloro-3,4-dihydro-2H-pyrano[3,2- |jb]pyridin-4-yl)urea X:4 x y.y / ' A —.. X / (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -( 1 -methyl -2- o''' " X o «— -*> A. A oxo- 1,2-dihydropyridin-4-yl)- 1H- A A A A > A T "" pyrazol-4-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-(pyridin-2- L I X>-O yl)thiazol-4-yl)urea xx / / (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- X' \, X b i A A A b]pyridin-4-yl)-3 -(2-( 1 -methyl- 1H- pyrazol-3-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(4-(2- Ay 1. A. - A £££ VZ- hydroxypropan-2-yl)phenyl)- 1H- y ■« \ ipyrazol-3-yl)urea x^l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- f 1. 1 £ / A VZ. b]pyridin-4-yl)-3 -( 1 -(4-((R)- 1, 1, 1 - trifluoro-2-hydroxypropan-2- f y v V " y yl)phenyl)- lH-pyrazol-3 -yl)urea,l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- J J A / b]pyridin-4-yl)-3 -( 1 -(4-((S)- 1, 1, 1 - « —■......ftrifluoro-2-hydroxypropan-2- yl)phenyl)- lH-pyrazol-3 -yl)urea(S)-4-(4-(3-(8-chloro-3,4-dihydro- 2Hpyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2- i Ay'' 1. ’y- Jl 'y JL \ / \, yl)benzamide-117- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(6-( 1 -cyclobutyl - 1 •3 jlH-pyrazol-4-yl)pyridin-2-yl)urea -X(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -cyclopropyl - 1 jl 1 AAA lH-imidazol-4-yl)thiazol-4-yl)urea T Y «(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 - 4 *. A r\ ■ / (difluoromethyl)- lH-pyrazol-4- '“'•s \ Vss»f 1» yl)thiazol-4-yl)urea A((S)- 1 -( 1 -(4-cyanophenyl)-lH- pyrazol-3-yl)-3-(8- methyl-3,4-dihydro-2H-pyrano[3,2- ii L YY - b]pyridin-4-yl)urea YY >'x((R)-l -( 1 -(4-cyanophenyl)- 1H- pyrazol-3-yl)-3- (8-methyl-3,4-dihydro-2H- J pyrano[3,2-b]pyridin-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- Ct"”b]pyridin-4-yl)-3-(2-(2-(2- ~\ 1 cyanopropan-2-yl)-2H- 1,2,3 -triazol- A4-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(3 -fluoro-4- (methylamino)phenyl)thiazol-4- C:yl)urea A(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(3 -fluoro-4-,fy7=Vhydroxyphenyl)thiazol-4-yl)urea ~ Y A...... / IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structurel-((S)-8-chloro-3,4-dihydro-2H- O'"'*pyrano[3,2- 1 sib]pyridin-4-yl)-3-(2-((S)-... 1 j rl '\ / / . \ l tetrahydrofuran-3 -yl)thiazol-4- yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-((R)- tetrahydrofuran-3 -yl)thiazol-4-. 1yl)urea H H / / . / \ \ / (R) - 1 -( 1 -(4-cyanophenyl) - 1 H- / \ y / _pyrazol-3-yl)-3- (3,4-dihydro-2H-pyrano[3,2- / *.b]pyridin-4-yl)urea w\(S)-l-(l -(4-cyanophenyl) - 1 H- \o. ■' / xpyrazol-3-yl)-3- i A(3,4-dihydro r XXi-2H-pyrano[3,2- b]pyridin-4-yl)urea / n(S)-l-(8-chloro-3,4-dihydro-2H- J r ii. pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -isopropyl- 1H- O V’ Z - pyrazol-4-yl)thiazol-4-yl)urea \ / ■■■■■■■ / / (S)-l-(8-chloro-3,4-dihydro-2H- X pyrano[3,2-.. V b]pyridin-4-yl)-3 -(2-( 1 -(2- cyanopropan-2-yl)- lH-pyrazol-3 - X A / — X! " A yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- ' ’7b]pyridin-4-yl)-3 -(2-( 1 -(2- cyanopropan-2-yl)- lH-pyrazol-4- if. A f-: / \ i - yl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -cyclopropyl - lH-pyrazol-4-yl)thiazol-4-yl)urea. X 1 1.>>■IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- / \ b]pyridin-4-yl)-3 -(2-( 1 -cyclopropyl - I A )A z ix f A / \ V < lH-pyrazol-4-yl)thiazol-4-yl)urea1 " " / A(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(6-cyanopyridin-2- yl)urea& / l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-( 1 -(( 1 s,3R)-3- hydroxy cyclobutyl) - 1 H-pyrazol-3 - M ) A' A N' * A yl)thiazol-4-yl)urea ' 1 / \ J(S)-l-(8-chloro-3,4-dihydro-2H- o'"a / esssai pyrano[3,2- / b]pyridin-4-yl)-3 -(4-(4- A k A A- cyanophenyl)oxazol-2-yl)urea 1 * * \1 -(2-((S)- 1 -hydroxyethyl)thiazol-4- / " Ayl)-3-((S)-8- / \ y z— methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea A A z v / / / 1 -(2-((S)- 1 -hydroxyethyl)thiazol-4- yl)-3-((R)-8- methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea. i 1 1 rA " Y A A \(S)-4-(3-(3-(8-chloro-3,4-dihydro- 2Hpyrano[ » A A / ‘sasy( 3,2-b]pyridin-4-yl)ureido)-lH- JI L zK~~A A. / H '■'VV--- ~ pyrazol- 1 -yl)-2-fluoro-N-methylbenzamide-120- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure (S)-4-(4-(3-(8-chloro-3,4-dihydro- 2Hpyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2- yl)-2-fluoro-N-methylbenzamide(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -( 1 -methoxy- 2-methylpropan-2-yl)-lH-pyrazol-4- yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -methyl- 1H- pyrazol-3-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(2- methylpyridin-4-yl)-lH-pyrazol-4- yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-(2- methyloxazol-5-yl)thiazol-4-yl)urea((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(4-((S)- 1 - hydroxyethyl)phenyl)thiazol-4- yl)urea((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(4-((R)- 1 - hydroxyethyl)phenyl)thiazol-4- yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(3,3 - difluorocyclobutyl) - 1 H-pyrazol-3 - yl)thiazol-4-yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure (S)-6-(3-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide4- [3 - [ [(4 S) -8 -chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4- yl] carbamoylamino]pyrazol- 1 -yl] -N- (2-hydroxyethyl)benzamide(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(6-( 1 -(oxetan-3 -yl)- lH-pyrazol-4-yl)pyridin-2-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(6-(l-(oxetan-3-yl)- lH-pyrazol-4-yl)pyri din-2 -yl)urea1 -(2-((R)-l-hydroxyethyl)thiazol-4- yl)-3-((R)-8- methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea1 -(2-((R)-l-hydroxyethyl)thiazol-4- yl)-3-((S)-8- methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea1 -[2-(4-hydroxyphenyl)thiazol-4-yl] - 3-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]urea1 -[2-(4-hydroxyphenyl)thiazol-4-yl] - 3-[rac-(4R)-8-chloro-3,4-dihydro-2H-pyrano [3,2-b] pyridin-4-yl] urea-122- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -cyclobutyl - Civ X r - i'A. ' i v s' r"'--. x \ / A 1 lH-pyrazol-4-yl)thiazol-4-yl)urea '..> X(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- / ""7 b]pyridin-4-yl)-3 -(2-( 1 -cyclobutyl - A A A. A”" AlH-pyrazol-4-yl)thiazol-4-yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-( 1 -(( 1 s,3 S)-3- i 1 "■ hydroxycyclobutyl)- lH-pyrazol-4- '•s,, AA x-XX '’•ANV? \yl)thiazol-4-yl)ureal-((R)-8-chloro-3,4-dihydro-2H- pyrano[3,2- rj b]pyridin-4-yl)-3 -(2-( 1 -(( 1 s,3 S)-3 - hydroxy cyclobutyl)- lH-pyrazol-4- X X / A! ' yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(3,5 - dimethylisoxazol-4-yl)thiazol-4-<:x A. / \ i yl)urea1 >■- / 4-[3-[[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b]pyridin-4- A, A 1. A i F 7-- / ' \ / -A A •. / \ yl]carbamoylamino]pyrazol- 1 - 7yl]benzamide4-[3-[[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b]pyridin-4- yl]carbamoylamino]pyrazol- 1 - yl] benzamide AxO O.(S)-l-(8-chloro-3,4-dihydro-2H-Xvx — -A.3 & \ Z'*-v xxA A*tpyrano[3,2- X r'" J. i x / -A r ■" b]pyridin-4-yl)-3 -(2-( 1 -(2- hydroxy ethyl)- lH-pyrazol-4- Xyl)thiazol-4-yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(R)-l-(8-chloro-3,4-dihydro-2H- •y’z\ > r'-'X A-' pyrano[3,2- L A / A i‘ b]pyridin-4-yl)-3 -(2-( 1 -(2- 1 1 Jhydroxyethyl)- lH-pyrazol-4- (Jyl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- 1 1 J lb]pyridin-4-yl)-3 -(2-( 1 -(2,2,2- trifluoroethyl)- lH-pyrazol-4- I Jvyl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- s — “'X -:: pyrano[3,2- I A z'"-£; r b]pyridin-4-yl)-3 -(2-( 1 -(2,2,2- trifluoroethyl)- lH-pyrazol-4- yl)thiazol-4-yl)urea L J(R)- 1 -(2-acetylthiazol-4-yl)-3-(8- methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4- yl)ureaxX 1 1 r1 r r \ A(R)- 1 -(2-acetylthiazol-4-yl)-3-(8- methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea f I 'yl' iTl i"' rx / \ (R)- 1 -(8-methyl-3,4-dihydro-2H- pyrano[3,2- / / b]pyridin-4-yl)-3-(2-(l-(oxetan-3-yl)- x A / Y l lH-pyrazol-4-yl)thiazol-4-yl)urea T >4(R)- 1 -(8-methyl-3,4-dihydro-2H- pyrano[3,2- 1 t b]pyridin-4-yl)-3-(2-(l-(oxetan-3-yl)- y i lH-pyrazol-4-yl)thiazol-4-yl)urea XIx -J-124- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4 \ Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- O''pyrano[3,2- r~'\ J b]pyridin-4-yl)-3-(2-(2-methyl-2H- ■x xl. < X zl,2,3-triazol-4-yl)thiazol-4-yl)urea \ i \(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-methyl-2H- l,2,3-triazol-4-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- f 1 ii / NA / 4-yl)-3-(2-(l-(2,2-difluoroethyl)-lH- A X A A A’X, / f pyrazol-4-yl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- z-A. X pyrano[3,2-b]pyridin- || > - Z4-yl)-3-(2-(l-(2,2-difluoroethyl)-lH- X. A A -. Z \ •' pyrazol-4-yl)thiazol-4-yl)urea1 -(6-(4-(2-aminopropan-2- yl)phenyl)pyridin-2-yl)-3 - (8-chloro-3,4-dihydro-2H- 1 'N A N. X NI'. pyrano[3,2-b]pyridin-4-yl)urea A(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-( 1 -(2 -methoxyethyl)- 1H- £X 'Y^"' pyrazol-4-yl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-( 1 -(2 -methoxyethyl)- 1H- X 1 Jpyrazol-4-yl)thiazol-4-yl)urea T T(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-(l-ethyl-lH-pyrazol-4- 1 1 1. A. Ayl)thiazol-4-yl)urea f "y Y HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 1 H li \4-yl)-3-(2-(l-ethyl-lH-pyrazol-4-! M'S. zA AAAM 4 yl)thiazol-4-yl)urea A(S)-l-(8-chloro-3,4-dihydro-2H- Lpyrano[3,2-b]pyridin- 4-yl)-3-(2-cyclopropylthiazol-4- ■; ivxyl)urea A I,r> <i N H ii(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- i i j r \ _ / A 4-yl)-3-(2-cyclopropylthiazol-4- v z'-\. jk xx A yl)urea T H 'V M '(R)-4-(3 -(3 -(8-chloro-3,4-dihydro- 2H-pyrano[3,2- b]pyridin-4-yl)ureido)- IH-pyrazol- 1 - V' '5p' V.-.k' \ yl)-N-((3 -methyloxetan-3 - ■'•sc?'yl)methyl)benzamide z5 (S)-4-(3-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2- ii 1 k — \ A b]pyridin-4-yl)ureido)- IH-pyrazol- 1 - yl)-N-((3 -methyloxetan-3 - ' ” ~ “A / yl)methyl)benzamide / ’"w>< / l-((R)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-((S)-l- Ci yhydroxyethyl)thiazol-4-yl)urea i H Hril-((R)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 1 II4-yl)-3-(2-((R)-l- hydroxyethyl)thiazol-4-yl)urea, A Il " AA •* \IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structurel-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-((S)-l- hydroxyethyl)thiazol-4-yl)urea, 1 X s-i A H AAA l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- A A 94-yl)-3-(2-((R)-l- ' C“‘l’" X A Ix, J 1 / “‘A, X hydroxyethyl)thiazol-4-yl)urea, 1 \ (R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- il f X^AA4-yl)-3-(2-(l-(3,3- Sidifluorocyclobutyl)- lH-pyrazol-4- 1 1 yl)thiazol-4-yl)urea A:f> ((S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(3,3 - difluorocyclobutyl)- lH-pyrazol-4- 1 T J..rL. A *** \ ’y-issfc i yl)thiazol-4-yl)urea M:(R)-6-(3-(8-methyl-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide, I X 1 A)A ” I (S)-6-(3-(8-methyl-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide n i n. Ali 1" Y A l-[rac-(4S)-8-chloro-3,4-dihydro-2H- | AX / Arpyr JA A / A\ A Aano[3,2-b]pyridin-4-yl]-3-[l-[4- 1 i [rac-( 1 R)-2,2,2-trifluoro- 1 -hydroxy- ethyl]phenyl]pyrazol-3-yl]urea-127- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structurel-[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] -3 - [ 1 - 1 _ / [4-[rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy-ethyl]phenyl]pyrazol-3 - VcCJ... yl]urea(R)- 1 -(2-(4-(2-aminopropan-2- yl)phenyl)thiazol-4- yl)-3-(8-chloro-3,4-dihydro-2H- k Jl 'si' '■? / / J 4 -Y \ pyrano[3,2-b]pyridin-4-yl)urea 1 * - 4(S)- 1 -(2-(4-(2-aminopropan-2- yl)phenyl)thiazol-4- 1. 1 f >-<" yjx yl)-3-(8-chloro-3,4-dihydro-2H-Z* ’Y Y \, pyrano[3,2-b]pyridin-4-yl)ureaSl-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4- " ii o t — 7 V X J" - N yl)-3-(2-(2-methyl-2H-l,2,3-triazol- 4-yl)thiazol-4-yl)urea(S)-4-(4-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2- 1 A.1 Ab]pyridin-4-yl)ureido)thiazol-2-yl)- fN -((3 -methyloxetan-3 - yl)methyl)benzamide 4'7 (R)-4-(4-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2-. A / b]pyridin-4-yl)ureido)thiazol-2-yl)- si ■O > «:• H y - - / / \ >,v» _ N -((3 -methyloxetan-3 - yl)methyl)benzamide4-(4-(3 -(8-chloro-3,4-dihydro-2H- 5 pyrano[3,2- H r\ A-. b]pyridin-4-yl)ureido)thiazol-2-yl)-2-U!J jl!! A— -4 / \ ''St''' ''V V / fluoro-N-methylbenzamide" I JIl-[(4S)-8-chloro-3,4-dihydro-2H-;;(j:< - pyrano[3,2-b]pyridin-4-yl] -3 -[ 1 -(4-cyanophenyl)pyrazol -3 -yl]urea-128- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name StructureY 4 i ■;■! rs""\ Z \ l-[(4R)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 -[ 1 -(4- cyanophenyl)pyrazol-3 -yl]urea T T _1 -(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4- yl)-3-(2-(2-hydroxypropan-2- y Ci i re / \ yl)thiazol-4-yl)urea 'y y y y \' z(R)-l-(6-(4-(3-aminooxetan-3- yl)phenyl)pyridin-2- yl)-3-(8-chloro-3,4-dihydro-2H- Cl-,. Z X' / s‘ > -A. xAx pyrano[3,2-b]pyridin-4-yl)urea 'I |f|; / \ _ ' ' 'V ■■ I Az 4.. / (S)-l-(6-(4-(3-aminooxetan-3- \ _, yl)phenyl)pyridin-2- \ / yl)-3-(8-chloro-3,4-dihydro-2H- > \pyrano[3,2-b]pyridin-4-yl)urea / J::::::::.C y / / / X / X / f A $! % l-[rac-(4S)-8-chloro-3,4-dihydro-2H- “x X A A 1 X~<~A / “ pyrano[3,2-b]pyridin-4-yl]-3-[l-[4- I Y 'r V 'V Y Z’Y z [rac-( 1 S)-2,2,2-trifluoro- 1 -hydroxy- x x ■ y ethyl]phenyl]pyrazol-3-yl]urea / l-[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] -3 - [ 1 - [4-[rac-( 1 S)-2,2,2-trifluoro- 1 - -xA 1 1 rvrA / •' hydroxy-ethyl]phenyl]pyrazol-3 - I "7 " A-'S'Ayl]urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl) -3 -(2-( 1 -(oxetan-3 -yl) - 1 H- pyrazol-4-yl)thiazol-4-yl)urea «....1 A X x x-y ""JIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl) -3 -(2-( 1 -(oxetan-3 -yl) - 1 H-. 1pyrazol-4-yl)thiazol-4-yl)u 1Al-(2-acetylthiazol-4-yl)-3-(8-chloro- 3,4-dihydro-2Hpyrano [ "1 if A\ / 3,2-b]pyridin-4-yl)urea A A J'' L "'-A A \L '-v'A.,'-'’ Jl-(3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2- 0 f A'\ / A ((R)-3 -hydroxypyrrolidin- 1 - yl)thiazol-4-yl)urea -v A A1 "3l-(3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2- o'" 05 if - 1 ((R)-3 -hydroxypyrrolidin- 1 - Av x A A \ 1 yl)thiazol-4-yl)urea I | »tSAn AAizA1 -[ 1 -[4-( 1 -amino- 1 -methyl - AX, / =^ ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- CK 1 > — <■ x / chloro-3,4-dihydro-2H-pyrano[3,2- 0A " b]pyridin-4-yl]urea1 -[ 1 -[4-( 1 -amino- 1 -methyl - ethyl)phenyl]pyrazol-3-yl]-3-[(4R)-8- Ak I X> A A ' V h:•< • A N \\ ch o o 3,4 d h — / r i •* / l - - ydro-2H-pyrano[3,2- \ b]pyridin -A--4-yl]urea3-[4-[[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b]pyridin-4- r "i i AY A / yl]carbamoylamino]thiazol-2-X-. xV Vv' yl]bicyclo [1.1.1 ]pentane- 1 - I NA carboxamideh _ / '-T k A '\IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO-131- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structure \ / s. r „ / VA O.-' ' ^.. / IS 1 > — \. / ! K A 'z,-“~ \ A A. x A \ A i A • T:f - iA 1 A -y,( ''A« / "r'Kf( >.A\ / .f-K. A. r / •i»fA^ A t A YJ f I K, ’AH Fj J lV r I JA I-, zJ il% ' L A 1s,, / \ \ -Mz,«»" < i! H H '"' \'<>8 A1 A.,1.. A. J-132- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 4Chemical Name Structure\ )'ji I 1 JA / X- 'A ££ 's<' A~ / \ VX \ / y „ - f\ / \ _ \ \ / ^% = J / \ / " O. k / \ X'-"-. xA'-'x.,,. A x X ek, JL JrA’ ''sA A-X Ay’5^ ”'N” A, A XX s ** / Oi. v n z- '•>< y 1 V x / r A-zXi.v t> kJ ” “ I A.oCi\ 'J ijJ M i « XX t '<? X A., / F \, i:0A ACS-X XX1 ’A's. 1 8 A zx J, A A- / “■•<.!" IlKH B \ X shIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structure0X0z"--' CK Z xL j }to. / \ ] i T H H \FK X>-‘Fz'. Oi » \.._z\z 'Sf' %''' Yr"’ X / > I “ "I I IL Xk- X MX '"v X / -jcZxx 1fifSSS-X.1 >^.z \.. _ \-zx 1 XX > HC V YN*-- / \ XXN" T<z-^X | YY / SKSS\ “yO jkU A >z.'X' / < / •' - Y~.; ' v;- / 7 \ \ ■0 | Z-'X X / / =:=^ \ «■!; X ') ■x fi> A H>z" A - / - -C \-j rv / *\ z v*W \ Z~t--134- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name StructureA, x>. - A A, 1 O A A H■M's s'' > S<zY'* i. -A. k 1 1 If \ Z T A ■*■ A A A'~A;X' ■<:: ■■"' A.,-" A A A \:::;:?4 1 1 - ’1 'xi j r\ XAZ^..1 1 1 / ;A"--~Y 1 AA; A AC A- A A. A ii J ii i \ \ i t 1 |fM— >, ’v Jk A. AC / A # V V Az" A.,,,,,,z: *£, f l 1.£1-0 A A *'%|A AA A)' 1,,,,, A A,? ^A \ O / K5555553^ ii J 1 A. X-. / ?A Xy / "^ A A " V %,,,,„ / _>;; Nx.■"IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 4Chemical Name Structureci.. rZ 1 &*1 X?* XL J " "’i | r\. "'v...-- "vZ<•ift 1 1 |T~\ / ''-'■-K'-'''tiX^, ■“A k,k i 0 ft Hsx“v.<st *> 1l„.•’A'" A j|", F \'; \ '(.■■■■^^ I?v - j. j Ift. J. J. If \ X 'VZ A / ?•■■■"•-<:-z W-'?T JIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0136] In another aspect, provided herein is a method of treating PMD in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by formula (V):Formula (V)or a pharmaceutically acceptable salt thereof, wherein:A is substituted di azole, oxazole, substituted oxazole, thiazole, substituted thiazole, thiadi azole, substituted thiadi azole, oxadi azole, substituted oxadi azole, tri azole, substituted triazole, pyridine or substituted pyridine;wherein when the substituted diazole is a pyrazole, the substitution is not an unsubstituted phenyl.

[0137] In some embodiments, the compound is a compound of formula (V) listed in Table 5.-137- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 5Chemical Name Structurel-| 1 -| 4-( 1 -hydroxy- 1- methyl- ethyl)phenyl]pyrazol-3 -yl] - 3-[rac-(lS)-l- cyclopropylethyl]urea1 - [2- [ 1 -( 1 -cyano- 1 -m ethyl - ethyl)imidazol-4-yl]thiazol- 0 -SX4-yl]-3-[rac-(lS)-l- cyclopropylethyl]urea A 1\ 1H T\ V / / .- / / H HxzJ dwe ww1 -[2-( 1,5 -dimethylpyrazol- 3 H MM3 -yl)thiazol -4-yl] -3 - [rac- o?(1S)-1- > / o=IZcyclopropylethyl]urea IZ \ 3^ 1 / 1l-[rac-(lS)-l- Xz:cyclopropylethyl] -3 - [ 1 - [2- ^Xz (trifluoromethyl)-4- pyridyl] pyrazol-3 -yl] ureao2F1 - t \i-~ 1 T] l-[rac-(lS)-l- h ' 1 "’IF\ F Tl Tl cyclopropylethyl] -3 -[ 1 - [5 - (trifluoromethyl)-3 - pyridyl]pyrazol-3-yl]urea =0r^\A A A\ / H Hl-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [6- (trifluoromethyl)-2- pyridyl] pyrazol-3 -yl] ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5 LL. LL. LL I li Chemical Name Structure j X X l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [4- (trifluoromethyl)-2- pyridyl] pyrazol-3 -yl] ureaIlCJ / l-[rac-(lS)-l- / U\cyclopropylethyl] -3 - [2 - [ 1 - 5 zx(2,2,2- >11111•<>-- zxtrifluoroethyl)pyrazol-3 - xz:TZyl]thiazol-4-yl]urea \\o°^^=zxII / IH>.-- xz XZl-[2-(l- \ IZcyclopropylimidazol-4-.o r-syl)thiazol-4-yl] -3 -[rac-( 1 S)- 1 -cyclopropylethyl]urea x I o =T \j K n M nNZ1l-[rac-(lS)-l- I II cyclopropylethyl]-3-[2-[4- J ff[rac-( 1 R)-2,2,2-trifluoro- 1 - 'V h Tl[I I hydroxy- ethyl]phenyl]thiazol-4- X IX Xyl]urea 1 "fl / Tl Tl ■n l-[rac-(lS)-l- cyclopropylethyl]-3-[2-[4- [rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy- ethyl]phenyl]thiazol-4- yl]ureal-[l-[3-fluoro-4-[rac-(lR)- 2,2,2-trifluoro- 1 -hydroxy- ethyl]phenyl]pyrazol-3 -yl] - 3-[rac-(lS)-l- cyclopropylethyl]ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5 LL Chemical Name J x--- ' 1 LL Structure1 -[ 1 -[3-fluoro-4-[rac-( 1 S)- 2,2,2-trifluoro- 1 -hydroxy- LL 1 ethyl]phenyl]pyrazol-3-yl]- 3-[rac-(lS)-l- cyclopropylethyl]ureal-[rac-(lS)-l- cyclopropylethyl] -3 -[ 1 - [3 - [rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy- 1 -methyl - ethyl]phenyl]pyrazol-3-.. zxyl]urea xzzxl-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [3 - (. ■'- xz xz HOJ / F[rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy- 1 -methyl - ethyl]phenyl]pyrazol-3- J zyl]urea? I L ( \N' N'' N '"zV H H1-[(1S)-1- 1 X H cyclopropylethyl] -3 -[2-( 1 - - O: -S. LI I L J o x N / methylpyrazol-3 -yl)thiazol- = J # A—Xr~ &~N4-yl]urea\ / H H "n T1 T1 l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [3 - [rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy- ethyl]phenyl]pyrazol-3- yl]ureaHO,F1-((S)-1- cyclopropylethyl)-3 -( 1 - (3 -((R)-2,2,2-trifluoro- 1 -. o / -■- / SF hydroxy ethyl)phenyl)- A JI XN’ \\1 H-pyrazol -3 -yl)urea V -Z N' ''N' 'NV H H-140- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structurel-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [3 - [rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy- ethyl]phenyl]pyrazol-3- yl]ureaHOF1-((S)-1- _ I _ p cyclopropylethyl)-3 -( 1 - i"f"i*" '"“■ / (3 -((S)-2,2,2-trifluoro- 1 -. IZ o / r-ixz F hydroxy ethyl)phenyl)- i II L. N {■' \\1 H-pyrazol-3 -yl)urea — N °= / N " N X / V H xz H xzl-[rac-(lS)-l- F F cyclopropylethyl]-3-[2-[4- o H z V (trifluoromethoxy)phenyl]t? jf J ) V - / hiazol-4-yl]urea ^xzVVX^~NH'A'NH''7"'N / l-[2-(l- bicyclo[l.1. l]pentanyl)thia L y xo.,zol-4-yl] -3 -[rac-( 1 S) - 1 - cyclopropylethyl]urea JL JL'T ’"-n V H H T] l-[l-[4- (methoxymethyl)phenyl]pyrazol-3 -yl] -3 -[rac-( 1 S ) - 1 - X 1 L Vy cyclopropylethyl]urea ry- 'N' -N'' NVH Hl-[l-[4-(2- hydroxyethyl)phenyl] pyrazol-3 -yl] -3 -[rac-( 1 S) - 1 - cyclopropylethyl]urea j- N -k N X N O VX --z. °“ vH H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 - [4- [(1R)-1- hy droxyethy 1] phenyl] pyrazol-3-yl]ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5 IL U- U. I x Chemical Name Structure p A 1-[(1S)-1- - - ““ cycl Aopropylethyl] -3 -[ 1 - [4- [(1S)-1- hy droxyethy 1] pheny 1] py raz A A A / A A / V N N N V H 1ol-3-yl]urea H H -Z \ \l z-[rac-(lR)-l- cyclopropylethyl] -3 -[ 1 -[4- [rac-( 1 S)-2,2,2-trifluoro- 1 - Q hydroxy- \zx zx ethyl]phenyl]pyrazol-3- yl]urea^ XZ^ zzl-[rac-(lR)-l- iiuiif— cyclopropylethyl] -3 -[ 1 -[4- IZ[rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy- ethyl]phenyl]pyrazol-3- yl]urea zl-[rac-(lS)-l-F\ F cyclopropylethyl] -3 -[ 1 -[4- [rac-( 1 R)-2,2,2-trifluoro- 1 - 1 II LFhydroxy- 1 -methyl - ethyl]phenyl]pyrazol-3- k TI- v n «N- / ' 'ohyl]urea-n i -j. ”T1 1 -((S)- 1 -cyclopropylethyl)- R F 3 -( 1 -(4 -(( S) - 1, 1, 1 -trifluoro- 2-hydroxypropan-2- yl)phenyl)- lH-pyrazol-3 - A, Jl XN\ k-Z”Fyl)urea \7 N NNAOH v n nl-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [4- [rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy- 1 -methyl - ethyl]phenyl]pyrazol-3- yl]urea-142- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure1 -((S)- 1 -cyclopropylethyl)- 3 -( 1 -(4-((R)- 1,1,1 -trifluoro- F 2-hydroxypropan-2- yl)phenyl)- lH-pyrazol-3 - i °,ryl)urea v vz ' nr T nN / OH l-[rac-(lS)-l- cyclopropylethyl] -3 -[ 1 -[6- [rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy-ethyl] -3 - pyridyl] pyrazol-3 -yl] urea V il mit H H / V~~FF > l-[rac-(lS)-l- cyclopropylethyl] -3 -[ 1 -[6- I 9 / ^N, OH [rac-( 1 S)-2,2,2-trifluoro- 1 - X ^°=hydroxy-ethyl] -3 - N N A N / Z Z _ / ZZ \ pyridyl] pyrazol-3 -yl] urea V H H zzF F l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 6 - [rac-(3S)-3- hydroxypyrrolidin- 1 -yl] -2- pyridyl]urea NbH l-[rac-(lS)-l- cyclopropylethyl] -3 - [6- 3 O[rac-(3R)-3- hydroxypyrrolidin- 1 -yl] -2- r IIpyridyl]urea N 'XVH H1 -(6-pyrrolidin- 1 -yl-2- pyridyl) -3 - [rac-( 1 S) - 1 - = ocyclopropylethyl]ureai x Jv V-Z^ N NH HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 5 o u. Chemical Name Structure, / A Z.. Q - ' 1-[(1S)-1- o $ cyclopropylethyl] -3 -[ 1 - [4-so r-y < V [(1R)-1- methylsulfonylethyl] phenyl A A A / NA AA ]pyrazol-3-yl]urea N V / \ V H H '' 1-[(1S)-1- cyclopropylethyl] -3 -[ 1 - [4- z[(1S)-1- methylsulfonylethyl] phenyl zz]pyrazol-3-yl]urea QZI ZI Ql-[rac-(lS)-l- \ °cyclopropylethyl] -3 -[ 1 -[4- ZI[rac-( 1 R)-2 zi4,2,2-trifluoro- 1 - A ilfln Zi— ZIhydroxy- A A / \\ ) — f ethyl]phenyl]pyrazol-3- V \ num / — / H H V-F yl]urea F F l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [4- [rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy- ethyl]phenyl]pyrazol-3- yl]urea1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -[4- = 0 ^ = °AA (ethyl sulfonylmethyl)phenyl]pyrazol-3-yl]urea A A A / NA A - / v H Hl-[l-(3- bromophenyl)pyrazol-3 - Br yl]-3-[rac-(lS)-l- = ocyclopropylethyl]urea i II L )r7' / 'Uz'N / A / \ / V H HN, N-dimethyl-6-[[rac-( 1 S)- 1- cyclopropylethyl] carbamoylamino]pyridine-2- carboxamideIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure1 -(6-phenyl-2-pyridyl)-3 - [rac-(lS)-l- cyclopropylethyl]urea1 I J / L zx " N ' ''N"' V % V H Hmethyl 3-[3-[[rac-(lS)-l- O cyclopropylethyl] carbamoylamino]pyrazol- 1 - / — ozyl]benzoatei iz T L, N— / \r—V H ^> O= X: _ / H3-[3-[[rac-(lS)-l- 0 cyclopropylethyl] carbamoylamino]pyrazol- 1 - l A / —OH yl]benzoic acid J zx'xzA A A W ) V H H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 - [3 - T1 fluoro-4- z (methylamino)phenyl] pyraz X’'x. ol-3-yl]urea2-fluoro-4-[3 -[ [rac-( 1 S ) - 1 - F cyclopropylethyl] carbamoylamino]pyrazol- 1 - yl]benzamide^ xN,tN X NA VAZ A A ’ VH Ho 1 - [ 1 - [4-(dimethylamino) -3 - F fluoro-phenyl]pyrazol-3 - yl]-3-[rac-(lS)-l- cyclopropylethyl]ureaV H HXIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure L l-(6-methyl-2-pyridyl)-3- [rac-(lS)-l- = ocyclopropylethyl]ureaX— < N N NV H HN, N -dimethyl-3 - [3 - [ [rac- 0(1S)-1- cyclopropylethyl] carbamoy KN lamino]pyrazol- 1 - Q1yl]benzamide I I ZIN N I N\ / H HN-methyl-3-[3-[[rac-(lS)- zr1- cyclopropylethyl] carbamoylamino]pyrazol- 1 - yl]benzamidel-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [4- (trifluoromethylsulfonyl)phenyl]pyrazol-3-yl]urea\ / n H O F 3-[3-[[rac-(lS)-l- 0 cyclopropylethyl] carbamoylamino] pyrazol - 1 - XNH2yl] benzamide = 0 r^\fA A / NX xV H Hl-[l-(4- cyclopropylsulfonylphenyl) 1 T 1 N— / \ _ H pyrazol-3-yl] -3-[rac-( 1 S) - 1 - cyclopropylethyl]urea VH H0 l-[l-(4- ethylsulfonylphenyl)pyrazol-3-yl]-3-[rac-(lS)-l- cyclopropylethyl]urea _A A A / A-146- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5 O Chemical Name Structure \\ l-[l-(3-methyl-4- X U- H methylsulfonyl- - 0 AA / ==== / 0 phenyl)pyrazol-3 -yl] -3 - 1 ° [rac-(lS)-l- i I x x xx cyclopropylethyl]urea V H H X 6l-[l-(4,4- difluorocyclohexyl)pyrazol 2-3 -yl] -3 - [rac-( 1 S ) - 1 - cyclopropylethyl]ureaMl-[l-[3- ZI(methylsulfonylmethyl)phe / — s — nyl] pyrazol-3 -yl] -3 - [rac- zx zx\ X °"=(1S)-1- cyclopropylethyl]urea l / tllll'—A A X W X<. - N \ _ / Vl-[l-[4- (methylsulfonylmethyl)phenyl] pyrazol-3 -yl] -3 - [rac- (1S)-1- cyclopropylethyl]ureal-[l-[4- [(dimethylamino)methyl]phenyl] pyrazol-3 -yl] -3 - [rac- x I X(1S)-1- ZNX \ _. cyclopropylethyl]urea VH H / N —l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [rac-(lS)-l- phenylethyl] pyrazol-3 - = O r^=\ X= / yl]urea? X XV-r N N N XNX \\ / H Hl-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [rac-(lR)-l- phenylethyl] pyrazol-3 - = oyl]urea AXX JI X- AxV HH-147- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure1 -( 1 -cyclohexylpyrazol -3 - yl)-3-[rac-(lS)-l- 5 0 f^\ / \ cyclopropylethyl]urea ji XV VT NN NW ' - / H H ) l-[rac-(lS)-l- E F cyclopropylethyl] -3 - [ 1 - [3 - (trifluoromethyl)phenyl] pyrazol-3-yl]urea 'y fI Him — II LZN—— ( \\ / H Hl-[l-(3- Cl chlorophenyl)pyrazol-3 -yl] - 3-[rac-(lS)-l- / xzcyclopropylethyl]ureaV A H A H X J Z) > XX 1 -[ 1 -(2-methoxy-4- pyridyl)pyrazol -3 -yl] -3 - [rac-(lS)-l- cyclopropylethyl]ureacyclopropylethyl] -3 -[ 1 - [3 - (methylsulfamoyl)phenyl]pyrazol-3-yl]urea4-[3-[[(lS)-l- cyclopropylethyl] carbamoylamino] pyrazol- 1 -y 1] -N - methyl-benzamidecyclopropylethyl] -3 -[ 1 -(4- methylsulfonylphenyl)pyrazol-3-yl]urea-148- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name StructureO1-[(1S)-1- UL = 0,6' - cyclopropylethyl] j.s.-W Q -3 -[ 1 -[4- (methylsulfamoyl)phenyl]p i l| i N / / U\-u-uli / yrazol-3-yl]urea N N N\ / H H \_y_1-[(1S)-1- C XJ 1 o |Ocyclopropylethyl] -3 -[ 1 -(3 - L / z methylsulfonylphenyl)pyrazol-3-yl]urea ZIzz / - Q^( o=1-[(1S)-1- cyclopropylethyl]-3-[2-(2- ZIpyridyl)thiazol-4-yl]urea / w1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -(2- 1 Cmethoxyphenyl)pyrazol -3 - yl]urea1-[(1S)-1- cyclopropylethyl] -3 - [2 -(3 -Ffluorophenyl)thiazol-4- yl]urea\ / H H1-[(1S)-1- cyclopropylethyl]-3-[2- 1 c(trifluoromethyl)thiazol-4- tyl]urea IVH1-[(1S)-1- cyclopropylethyl]-3-[2-(4- pyridyl)thiazol-4-yl]urea 5 0 / ^\\ V — 7 N N NH H-149- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure cyclopropylethyl]-3-[2-(4- fluorophenyl)thiazol-4- yl]ureaFcyclopropylethyl]-3-[2-(2- fluorophenyl)thiazol-4- = o / A yl]urea^>1111><—■V H H*1I"‘ ' zzA °1 -( 1 -benzylpyrazol-3 -yl) -3 - ZIhli / ...- xzcyclopropylethyl]ureaA l XvY N N" N \ _V H H zz / " A\ 7 1-[(1S)-1- cyclopropylethyl] -3 - [2 -(3 - pyridyl)thiazol-4-yl]urea■n cyclopropylethyl]-3-(2- methylthiazol-4-yl)urea1-[(1S)-1- cyclopropylethyl] -3 -( 1 - pyrimidin-2-ylpyrazol-3 - yl)urea I I?N— / VH HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure0— cyclopropylethyl] -3 -[ 1 - (3,4- dimethoxyphenyl)pyrazol- 3-yl]ureaV H H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -F\F(2,2,2- Btrifluoroethyl)pyrazol-3 - 0f^\ F yl]urea i L.,N'— / N N VNH H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -(4- fluoro-3 -methyl - phenyl)pyrazol-3 -yl]ureaV H H1-[(1S)-1- p— cyclopropylethyl] -3 -[ 1 -(4- fluoro-3 -methoxy- phenyl)pyrazol-3-yl]urea A A AV H H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -(3 - methoxyphenyl)pyrazol -3 - I JI L N A \ yl]urea V7ZXN'ANZ XNV H Ho1-[(1S)-1- F cyclopropylethyl] -3 - [ 1 - (2,2-difluoroethyl)pyrazol- 4-yl]ureaA A XZN~ / V H H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -(4- methoxyphenyl)pyrazol -3 - yl]urea T — f N N N V / \V H HxIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5Chemical Name Structure cyclopropylethyl]-3-(4- = 0 O"-\ / ==\ phenyloxazol-2-yl)urea 1 A zV N^ N' NH H zcyclo V / Xpropylethyl]-3-(2- phenyltriazol-4-yl)urea zz / — / - fKif " / \ w —IZ IZcyclopropyle n tiim— Xthyl] -3-(5- phenyl- 1,3,4-oxadiazol-2- g \ \ c - _ )N,yl)u i yrea xzH Az= VH / \ cyclopropylethyl]-3-(2- phenylthiazol-4-yl)ureaHcyclopropylethyl] -3-(5- phenyl- 1,2,4-oxadiazol-3 - yl)ureacyclopropylethyl] -3-(5- ICphenyl- 1,3,4-thiadiazol-2- i yl)urea \ / NV Hcyclopropylethyl] -3 -[ 1 -(4- Ic5r’A pyridyl)pyrazol-3-yl]urea f L ANA, N N' N V_ / H V HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOChemical Name Structure cyclopropylethyl] -3-(5-?cphenyloxazol-2-yl)urea5rvz^x H / \ / >,-N cyclopropylethyl]-3-(2- A \phenylthiazol-5 -yl)urea zx zx_ / / -ilm u \ “H zz ZIIZ IIHIO / — 111 If <f—\ Z’X - > N^\ cyclopropylethyl] -3 -( 1 - phenylimidazol-4-yl)ureaxz A / M ) Nv¥_ / Hz cyclopropylethyl] -3 -( 1 - IcZ phenylimidazol-4-yl)urearY VVHs0 cyclopropylethyl] -3 -[ 1 -(2- pyridyl)pyrazol-3-yl]ureaA A A / N) y-Y N N NV H HNcyclopropylethyl]-3-(4- phenylthiazol-2-yl)urea iVHcyclopropylethyl] -3 -( 1 - pyrimidin-5 -ylpyrazol-3 - yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 5Chemical Name Structure1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -(3 - pyridyl)pyrazol-3-yl]ureaz1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -(4-?0Qfluorophenyl)pyrazol-3 - ziyl]urea _ N N N 1 # —FV mii ii H \ ~ZT zz H1-[(1S)-1- IZcyclopropylethyl] -3 -[ 1 -(3 - Hl n F fluorophenyl)pyrazol-3 - \ « _> / === / yl]ureaw / zz 1 N~Z \H1-[(1S)-1- cyc opZx l ropylethyl] -3 -[ 1 -(2- F fluorophenyl)pyrazol-3 - yl]ureaL A / NA ) N N X; _ / H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 - F (3,4- difluorophenyl)pyrazol -3 - yl]ureav H H1-[(1S)-1- cyclopropylethyl] -3 -[ 1 -[2- (dimethylamino)ethyl]pyra 5Czol-3-yl]urea fVH-154- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOChemical Name Structurecyclopropylethyl] -3 -( 1 - I(>rN phenylpyrazol-4-yl)urea 1 1 N— Z \' N" '^ _ / H Hcyclopropylethyl] -3 -( 1 - phenylpyrazol-4-yl)urea\ZI IZcyclopropylethyl] -3 -[ 1 -[2-. ^o> / w>= —(dimethylamino)ethyl]pyra IZ / — u zol-3-yl]urea 1J IyN — / \VV VNH H fl Jj z z1-[(1S)-1- cyclopropylethyl] -3-(5- methyl- 1 -phenyl -pyrazol-3 - yl)urea ~ c ) 7=^1 N— Z \ VAH H1-[(1R)-1- cyclopropylethyl] -3-(5- / methyl- 1 -phenyl -pyrazol-3 - yl)urea IcL X ) V 'H H1-[(1R)-1- cyclopropylethyl]-3-(4- methyl- 1 -phenyl -pyrazol-3 - yl)ureaIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 5 u.K,u. t Chemical Name Structure1 -(4-m ethyl- 1 -phenyl- LJ pyrazol-3-yl)-3-[rac-( 1 S) - 1 - - O cyclopropylethyl]urea Z O1 II LN 1A > — r ^ N" ' N' 'N / \ / \ / H Hz V£*i"' "-■ L / :zizKzx ° F xzE, F O IZ*7==== / 7\ A 1 v ^ A coV VT N^N^zCO<vN \|^H HMF' z Z — ■ A< V— Z^ i'N'^ I N'^ Ji N / — 7 QV»N pfH H / V ■" X -n^\^ T1 T1 T1 T1?O r^\T V — 7 N N IN / 7 \ H H \ = 9 HOV-A A^N'^ AXNXA V ^'N / NAH H AA 1A\ UA-0IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO Table 5Chemical Name Structure„ AN1NX:" C / - °" v H H v_z \ llHi "TZvAa..°,i> OH IZcH 'H- \ -Q C J-y- ™_ V~_ / N N N N A # V \~OH V H H o 2F A"A A A AO -A°HV H H F FF FIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5 X o Chemical Name Structure(S)- 1 -( 1 -cyclopropylethyl)- = O3 -( 1 -(5 -(2-hydroxypropan- 2-yl)pyridin-2-yl)-lH- i II LZN - < V / pyrazol-3-yl)urea X V — 7 N N IN A \ H H ' (S)- 1 -( 1 -cyclopropylethyl)- = 0 r^\ / ^N3 -( 1 -(6-(2-hydroxypropan- 2-yl)pyridin-3 -yl) - 1 H- i |[ 1 N — / \ _ / pyrazol-3-yl)urea V H H U / ' 1 -[2-[6-( 1 -hydroxy- 1 - methyl-ethyl)-3- pyridyl]thiazol-4-yl]-3- [rac-(lS)-l- / zxcyclopropylethyl]urea.. —l-[2-[4-(l- hydroxycyclopropyl)phenyl § 0 HO ]thiazol-4-yl]-3-[rac-( 1 S)- 1 -cyclopropylethyl]ureaV H H V l-[l-[4-(l- hydroxycyclopropyl)phenyl = 9 / ^\ HO ]pyrazol-3 -yl] -3 -[rac-( 1 S)- i J L V\ 1 -cyclopropylethyl]ureaV H HVl-[rac-(lS)-l- OH cyclopropylethyl] -3 - [ 1 - [2-c1 7 [rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy- 1 -methyl -ethyl] -4- pyridyl] pyrazol-3 -yl] urea = 0 / ==< c Jk / / NV N N N H H V_ / l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [2- 9HF [rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy- 1 -methyl -ethyl] -4- pyridyl] pyrazol-3 -yl] urear—f xk N JL N' A» N. / N\ \ _ / 7 / NV H HIPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 5 x u- Chemical Name Structure o 1 - [ 1 - [4-(3 -hydroxyoxetan- 3 -yl)phenyl]pyrazol-3 -yl] -?? / ^HO3-[rac-(lS)-l- t 1 L Mcyclopropylethyl]urea ~ N N N VZ r \ \ / H H t— -O l-[rac-(lS)-l- cyclopropylethyl] -3 - [ 1 - [6- Z[rac-( 1 R)-2,2,2-trifluoro- 1 - hydroxy- 1 -methyl -ethyl] -3 - pyridyl] pyrazol-3 -yl] urea\ QzxXZl-[rac-(lS)-l- \cyclopropylethyl] -3 - [ 1 - [6- =o9= / ~Ni [rac-( 1 S)-2,2,2-trifluoro- 1 - 1 I IZ L / Ahydroxy- 1 -methyl -ethyl] -3 - pyridyl] pyrazol-3 -yl] urea VH H / V~F F FA1-[(1S)-1- Zcyclopropylethyl] -3 -[ 1 - [5 - [( 1 R)-2, 2, 2 -trifluoro- 1 - A Xhydroxy- 1 -methyl -ethyl] -2- XAX XXOHpyridyl]pyrazol-3-yl]urea V H H V-F F F1-[(1S)-1- cyclopropylethyl] -3 -[ 1 - [5 - [( 1 S)-2,2,2-trifluoro- 1 - ' ”ni o X T1 hydroxy- 1 -methyl -ethyl] -2- pyridyl] pyrazol-3 -yl] ureal-[rac-(lS)-l- F cyclopropylethyl] -3 - [2- [ 1 - (2,2,2-. O r-S trifluoroethyl)imidazol-4- yl]thiazol-4-yl]ureaFV H MN

[0138] In some embodiments, the compound is present in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. In some embodiments, the compound or composition is administered orally, intrathecally, enterally, or intravenously.

[0139] In some embodiments, the PMD or MDDS is inherited.-159- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0140] In some embodiments, the subject has one or more of: mtDNA deletions, mtDNA mutations, impaired mitochondrial oxidative phosphorylation, impaired recycling of mtDNA nucleotides, a reduction in the amount of mtDNA, impaired mtDNA function, impaired replication of mtDNA, impaired mechanisms of mtDNA, unbalanced nucleotide pools, low processivity, a defect in DNA-binding function, decreased DNA-binding affinity, reduced catalytic efficiency, a reduction in thymidine kinase activity, a reduction in Twinkle helicase activity, a reduction in thymidine phosphorylase activity, a reduction in deoxyguanosine kinase activity, a reduction in Ribonucleotide reductase M2B activity, a reduction in ribonuclease Hl (RNASEH1) activity, a reduction in mitochondrial SSBP1 activity, a reduction in Mitochondrial Genome Maintenance Exonuclease 1 (MGME1) activity, a reduction in DNA2 nuclease / helicase activity, a reduction in adenine nucleotide translocase type 1 (ANTI) protein activity, a reduction in succinyl-CoA ligase (SUCL) activity, a reduction in MP VI 7 protein activity, a reduction in activity of ATP synthase enzyme, or any combination thereof.

[0141] In some embodiments, the subject has a mutation in the gene selected from the group consisting of thymidine kinase 2 (TK2), twinkle (TWNK or C10ORF2), TYMP, DGUOK, RRM2B, RNASEH1, Single Stranded DNA Binding Protein 1 (SSBP1), Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA2, ANTI (SLC25A4), SUCLG1, SUCLA2, MPV17, MT-ATP6, MT-TL1, MT-TH, and MT-TS1.

[0142] In some embodiments, (a) the subject has a mutation in the TK2 gene; and (b) the MDDS is thymidine kinase 2 deficiency (TK2D).

[0143] In some embodiments, the subject has unbalanced nucleotide pools.

[0144] In some embodiments, (a) the subject has a mutation in the TWNKLE gene; and (b) the MDDS is infantile onset spinocerebellar ataxia (IOSCA), ataxia neuropathy spectrum, infantile-onset spinocerebellar ataxia, or progressive external ophthalmoplegia.

[0145] In some embodiments, (a) the subject has a mutation in the TYMP gene; and (b) the MDDS is mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

[0146] In some embodiments, (a) the subject has a mutation in the DGUOK gene; and (b) the MDDS is Deoxyguanosine kinase (DGUOK) deficiency.-160- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0147] In some embodiments, (a) the subject has a mutation in the RRM2B gene; and (b) the MDDS is encephalomyopathic form with renal tubulopathy (RRM2B-MDDS).

[0148] In some embodiments, (a) the subject has a mutation in the RNASEH1 gene; and (b) the MDDS is a mitochondrial DNA maintenance disorder, adult-onset mitochondrial encephalomyopathy, or type 1 diabetes.

[0149] In some embodiments, (a) the subject has a mutation in the SSBP1 gene; and (b) the MDDS is Optic Atrophy 13 With Retinal and Foveal Abnormalities or Cone-Rod Dystrophy 2.

[0150] In some embodiments, (a) the subject has a mutation in the MGME1 gene; and (b) the MDDS is mitochondrial DNA depletion syndrome type 11 (MTDPS11).

[0151] In some embodiments, (a) the subject has a mutation in the DNA2 gene; and (b) the MDDS is progressive muscular dystrophy, progressive myopathy, or mitochondrial DNA depletion syndrome due to impaired replication and repair mechanisms of the mitochondrial DNA.

[0152] In some embodiments, (a) the subject has a mutation in the ANTI (SLC25A4) gene; and (b) the MDDS is Progressive external ophthalmoplegia (PEO), Cardiomyopathy and skeletal myopathy, Mitochondrial DNA depletion syndrome 12A (MTDPS-12A), Bipolar disorder, exercise intolerance, hyperlactatemia, cataracts, arterial hypertension, depression, or scoliosis.

[0153] In some embodiments, (a) the subject has a mutation in the SUCLG1 gene; and (b) the MDDS is SUCLG1 -related mitochondrial DNA (mtDNA) depletion syndrome.

[0154] In some embodiments, (a) the subject has a mutation in the SUCLA2 gene; and (b) the MDDS is Mitochondrial DNA depletion syndrome or Pyruvate dehydrogenase El-alpha deficiency.

[0155] In some embodiments, (a) the subject has a mutation in the MP VI 7 gene; and (b) the MDDS is MPV17-related hepatocerebral mitochondrial DNA depletion syndrome.

[0156] In some embodiments, (a) the subject has a mutation in the MT-TL1 gene; and (b) the MDDS is Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS).-161- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0157] In some embodiments, (a) the subject has a mutation in the MT-TL1 gene, the MT-TH, the MT-TS1 gene, or any combination thereof; and (b) the MDDS is Myoclonic Epilepsy and Ragged Red Fibers (MERRF).

[0158] In some embodiments, (a) the subject has a mutation in the MT-ATP6 gene; and (b) the MDDS is neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

[0159] In some embodiments, administration of the compound of formula I, II, III, IV, or V or a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof: (a) results in upregulating levels of mitochondrial DNA (mtDNA) in the subject; (b) results in dose-dependent increases in mtDNA production in the subject; (c) improves mtDNA recovery following depletion in the subject; (d) results in an increase in mtDNA production in the subject; (e) results in an increase in mtDNA copy number per cell in the subject; (f) results in restoration of mtDNA levels in the subject, and related improvement in cellular function; (g) results in an increase in mtDNA production in subject-derived fibroblasts; (h) increases cellular respiration in the subject; (i) results in an increase in cellular energy in the subject; (j) results in improved mitochondrial oxidative phosphorylation in the subject; (k) results in improved recycling of mtDNA nucleotides in the subject; (1) results in improved mtDNA function in the subject; (m) results in improved replication of mtDNA in the subject; (n) results in improved mechanisms of mtDNA in the subject; (o) shifts ATP production rate to favor oxidative phosphorylation in the subject; (p) results in improved liver health for the subject; (r) results in improved catalytic efficiency in the subject; (s) results in an increase in thymidine kinase activity; (t) results in an increase in Twinkle helicase activity; (u) results in an increase in thymidine phosphorylase activity; (v) results in an increase in deoxyguanosine kinase activity; (w) results in an increase in Ribonucleotide reductase M2B activity; (x) results in an increase in ribonuclease Hl (RNASEH1) activity; (y) results in an increase in mitochondrial SSBP1 activity; (z) results in an increase in Mitochondrial Genome Maintenance Exonuclease 1 (MGME1) activity; (aa) results in an increase in DNA2 nuclease / helicase activity; (bb) results in an increase in adenine nucleotide translocase type 1 (ANTI) protein activity; (cc) results in an increase in succinyl-CoA ligase (SUCL) activity; (dd) results in an increase in MP VI 7 protein activity; (ee) results in an increase in activity of ATP synthase enzyme: or (ff) any combination thereof.-162- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0160] In some embodiments, upregulation of healthy mtDNA in the subject occurs in multiple organs, including the brain.

[0161] In some embodiments, the increase in the mtDNA level in the subject is by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, as compared to the mtDNA level present in the subject prior to administration of the compound of formula I, II, III, IV, or V, or the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

[0162] In some embodiments, an increase in the mtDNA level in the subject is measured using a clinically acceptable technique. For example, the clinically acceptable technique includes, but is not limited to, PCR, Quantitative PCR (qPCR), digital PCR (dPCR), genomic methods such as whole exome sequences (WES) and whole genome sequencing (WGS), Low pass whole genome sequencing (IpWGS), and any combination thereof.

[0163] In some embodiments: (a) the method improves the processivity and / or activity of an enzyme or protein in the subject by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, as compared to activity of the enzyme prior to administration of the compound of formula I, II, III, IV, or V or the compound of Table 1, Table 2, Table 3, Table 4, or Table 5; and (b) the enzyme or protein is selected from the group consisting of Twinkle helicase, thymidine phosphorylase, deoxyguanosine kinase, Ribonucleotide reductase M2B, ribonuclease Hl (RNASEH1), mitochondrial SSBP1, Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA2 nuclease / helicase, adenine nucleotide translocase type 1 (ANTI) protein, succinyl-CoA ligase (SUCL), MP VI 7 protein, and ATP synthase enzyme.

[0164] In some embodiments, the improvement in the processivity or activity of the protein or enzyme in the subject is measured using a clinically acceptable technique.-163- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0165] In some embodiments, the mtDNA copy number per cell in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% as compared to the mtDNA copy number per cell present in the subject prior to administration of the compound of formula I, II, III, IV, or V or the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

[0166] In some embodiments, the improved liver health for the subject is determined by: (a) comparing the amount of liver enzymes and / or liver mtDNA in the subject prior to treatment and following treatment; (b) identifying a decreased presence of liver disease markers; or (c) any combination thereof.

[0167] In some embodiments, the therapeutically effective amount of the compound is a dose ranging from about 5 mg up to about 2000 mg. In some embodiments, the therapeutically effective amount of the compound is a dose of about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, about 500 mg, about 525 mg, about 550 mg, about 575 mg, about 600 mg, about 625 mg, about 650 mg, about 675 mg, about 700 mg, about 725 mg, about 750 mg, about 775 mg, about 800 mg, about 825 mg, about 850 mg, about 875 mg, about 900 mg, about 925 mg, about 950 mg, about 975 mg, about 1000 mg, about 1025 mg, about 1050 mg, about 1075 mg, about 1100 mg, about 1125 mg, about 1150 mg, about 1175 mg, about 1200 mg, about 1225 mg, about 1250 mg, about 1275 mg, about 1300 mg, about 1325 mg, about 1350 mg, about 1375 mg, about 1400 mg, about 1425 mg, about 1450 mg, about 1475 mg, about 1500 mg, about 1525 mg, about 1550 mg, about 1575 mg, about 1600 mg, about 1625 mg, about 1650 mg, about 1675 mg, about 1700 mg, about 1725 mg, about 1750 mg, about 1775 mg, about 1800 mg, about 1825 mg, about 1850 mg, about 1875 mg, about 1900 mg, -164- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOabout 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg. In some embodiments, the therapeutically effective amount of the compound is a dose ranging from about 30 to about 1000 mg.

[0168] In some embodiments, the therapeutically effective amount of the compound is a dose ranging from 5 mg / kg up to about 1000 mg / kg. In some embodiments, the therapeutically effective amount of the compound is a dose of about 5 mg / kg, about 10 mg / kg, about 15 mg / kg, about 20 mg / kg, about 25 mg / kg, about 30 mg / kg, about 35 mg / kg, about 40 mg / kg, about 45 mg / kg, about 50 mg / kg, about 55 mg / kg, about 60 mg / kg, about 65 mg / kg, about 70 mg / kg, about 75 mg / kg, about 80 mg / kg, about 85 mg / kg, about 90 mg / kg, about 95 mg / kg, about 100 mg / kg, about 125 mg / kg, about 150 mg / kg, about 175 mg / kg, about 200 mg / kg, about 225 mg / kg, about 250 mg / kg, about 275 mg / kg, about 300 mg / kg, about 325 mg / kg, about 350 mg / kg, about 375 mg / kg, about 400 mg / kg, about 425 mg / kg, about 450 mg / kg, about 475 mg / kg, about 500 mg / kg, about 525 mg / kg, about 550 mg / kg, about 575 mg / kg, about 600 mg / kg, about 625 mg / kg, about 650 mg / kg, about 675 mg / kg, about 700 mg / kg, about 725 mg / kg, about 750 mg / kg, about 775 mg / kg, about 800 mg / kg, about 825 mg / kg, about 850 mg / kg, about 875 mg / kg, about 900 mg / kg, about 925 mg / kg, about 950 mg / kg, about 975 mg / kg, or about 1000 mg / kg.

[0169] In some embodiments, the compound is administered once per day. In some embodiments, the therapeutically effective amount of the compound is below the nonclinical no-observed-adverse-effect level (NOAEL).

[0170] In some embodiments, the method results in improvement in one or more symptoms of the MDDS disorder. In some embodiments, the improvement one or more symptoms is measured using a clinically acceptable method.

[0171] In some embodiments, the symptom is selected from the group consisting of muscle function, muscle weakness, muscle atrophy, hypotonia, dystonia, loss of muscle coordination, loss of motor skills, sensory ataxia, epilepsy, encephalopathy with seizures, involuntary movements, seizures, status epilepticus, epilepsia partialis continua, focal motor seizures, generalized status epilepticus, refractory convulsive status epilepticus, progressive weakness of the extraocular muscles, bilateral symmetrical ptosis, ptosis, ataxia, parkinsonism, liver function, liver disease, hepatopathy, hepatic impairment, hypoglycaemia,-165- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOhepatic steatosis, developmental delay, growth retardation, gastrointestinal issues, weight loss, nausea, vomiting, diarrhea or persistent diarrhoea, cachexia related to gastrointestinal dysmotility, dysphagia, cerebellar ataxia, brain abnormalities, neurodevelopmental regression, myopathies, eye problems, ophthalmoplegia, cataracts, strabismus, optic atrophy, external ophthalmoplegia, hearing loss, sensorineural hearing impairment or deafness, cardiac problems, cardiomyopathies, heart disease, visual problems, retinopathy, renal dysfunction, renal disease, diabetes mellitus, proximal myopathy, encephalomyopathy, neuropathy, peripheral neuropathy, sensory neuropathy, distal myopathy, demyelinating neuropathy, neuropathic pain, exercise intolerance, lactic acidosis, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures, hypothermia, hypoglycemia, myoclonus, myopathy, depression, dysarthria, premature menopause, ragged-red muscle fibres, lipodystrophy, and any combination thereof.

[0172] In some embodiments, the subject to be treated is: (a) a pediatric patient; (b) an adolescent or young adult; or (c) an adult.III. Definitions

[0173] As used herein, “about” will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, “about” will mean up to plus or minus 10% of the particular term.

[0174] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate the embodiments and does not-166- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOpose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.

[0175] As used herein, comparative terms as used herein, such as higher, lower, increase, decrease, reduce, or any grammatical variation thereof, can refer to certain variation from the reference. In some embodiments, such variation can refer to about 10%, or about 20%, or about 30%, or about 40%, or about 50%, or about 60%, or about 70%, or about 80%, or about 90% or more higher than the reference. In some embodiments, such variation can refer to about 1%, or about 2%, or about 3%, or about 4%, or about 5%, or about 6%, or about 7%, or about 8%, or 0%, or about 10%, or about 20%, or 30%, or 40%, or 50%, or 60%, or 70%, or 75%, or 80%, or 85%, or 90%, or about 95%, or about 96%, or about 97%, or about 98%, or about 99% of the reference.

[0176] “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.

[0177] As used herein, “and / or” refers to and encompasses any and all possible combinations of one or more of the associated listed items, as well as the lack of combinations when interpreted in the alternative (“or”).

[0178] As used herein, the “administration” of an agent or drug to a subject includes any route of introducing or delivering to a subject a compound to perform its intended function. Administration can be carried out by any suitable route, including but not limited to, orally, intranasally, parenterally (intravenously, intramuscularly, intraperitoneally, or subcutaneously), rectally, intrathecally, or topically. Administration includes selfadministration and the administration by another.

[0179] As used herein, a "control" is an alternative sample used in an experiment for comparison purpose. A control can be "positive" or "negative." For example, where the purpose of the experiment is to determine a correlation of the efficacy of a therapeutic agent for the treatment for a particular type of disease, a positive control (a compound or composition known to exhibit the desired therapeutic effect) and a negative control (a subject or a sample that does not receive the therapy or receives a placebo) are typically employed.-167- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0180] As used herein, the term “effective amount” refers to a quantity sufficient to achieve a desired therapeutic and / or prophylactic effect, e.g., an amount which results in the prevention of, or a decrease in a disease or condition described herein or one or more signs or symptoms associated with a disease or condition described herein. In the context of therapeutic or prophylactic applications, the amount of a composition administered to the subject will vary depending on the composition, the degree, type, and severity of the disease and on the characteristics of the individual, such as general health, age, sex, body weight and tolerance to drugs. The skilled artisan will be able to determine appropriate dosages depending on these and other factors. The compositions can also be administered in combination with one or more additional therapeutic compounds. In the methods described herein, the therapeutic compositions can be administered to a subject having one or more signs or symptoms of a disease or condition described herein.

[0181] As used herein, a “therapeutically effective amount” of a composition refers to composition levels in which the physiological effects of a disease or condition are ameliorated or eliminated. A therapeutically effective amount can be given in one or more administrations. In some embodiments, an “effective amount” is an amount sufficient to effect beneficial or desired results. An effective amount can be administered in one or more administrations, applications, or dosages. Such delivery is dependent on a number of variables including the time period for which the individual dosage unit is to be used, the bioavailability of the therapeutic agent, the route of administration, etc. It is understood, however, that specific dose levels of the therapeutic agents disclosed herein for any particular subject depends upon a variety of factors including the activity of the specific compound employed, bioavailability of the compound, the route of administration, the age of the animal and its body weight, general health, sex, the diet of the animal, the time of administration, the rate of excretion, the drug combination, and the severity of the particular disorder being treated and form of administration. These considerations, as well as effective formulations and administration procedures are well known in the art and are described in standard textbooks.

[0182] The terms “pharmaceutically-acceptable,” “physiologically-tolerable,” and grammatical variations thereof, as they refer to compositions, carriers, diluents, and reagents, are used interchangeably and represent that the materials are capable of administration to or -168- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOupon a subject without the production of undesirable physiological effects to a degree that would prohibit administration of the composition. For example, “pharmaceutically-acceptable excipient” means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and desirable, and includes excipients that are acceptable for veterinary use as well as for human pharmaceutical use. Such excipients can be solid, liquid, semisolid, or, in the case of an aerosol composition, gaseous. “Pharmaceutically-acceptable salts and esters” means salts and esters that are pharmaceutically-acceptable and have the desired pharmacological properties. Such salts include salts that can be formed where acidic protons present in the composition are capable of reacting with inorganic or organic bases. Suitable inorganic salts include those formed with the alkali metals, e.g., sodium and potassium, magnesium, calcium, and aluminum. Suitable organic salts include those formed with organic bases such as the amine bases, e.g., ethanolamine, diethanolamine, triethanolamine, tromethamine, Nmethylglucamine, and the like. Such salts also include acid addition salts formed with inorganic acids (e.g., hydrochloric and hydrobromic acids) and organic acids (e.g., acetic acid, citric acid, maleic acid, and the alkane- and arene-sulfonic acids such as methanesulfonic acid and benzenesulfonic acid). Pharmaceutically acceptable esters include esters formed from carboxy, sulfonyloxy, and phosphonoxy groups present in the compound, e.g., Ci-6 alkyl esters. When there are two acidic groups present, a pharmaceutically acceptable salt or ester can be a mono-acid-mono-salt or ester or a di-salt or ester; and similarly where there are more than two acidic groups present, some or all of such groups can be salified or esterified. A person of ordinary skill in the art, would have no difficulty determining the appropriate timing, sequence, and dosages of administration for particular drugs and compositions of the present disclosure.

[0183] The term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal compounds, isotonic and absorption delaying compounds, and the like, compatible with pharmaceutical administration. Pharmaceutically acceptable carriers include ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances, such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal-169- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat. Pharmaceutically acceptable carriers and their formulations are known to one skilled in the art and are described, for example, in Remington's Pharmaceutical Sciences (20thedition, ed. A.Gennaro, 2000, Lippincott, Williams & Wilkins, Philadelphia, Pa.).

[0184] As used herein, the terms “subject”, “patient”, or “individual” can be an individual organism, a vertebrate, a mammal, or a human. In some embodiments, the subject, patient, or individual is a human. In some aspects, the subject is a mammal selected from a canine, a feline, an equine, a simian, or other. The methods can be used to treat non-human animals or to test for new or combination therapies when in an acceptable animal model.

[0185] The term “in need thereof’ would be a subject known or suspected of having or at risk of developing a disease or disorder characterized by unbalanced nucleotide pools, Primary Mitochondrial Disorder (PMD), mitochondrial disease, mitochondrial DNA depletion syndrome (MDDS), or a muscle myopathy disease (e.g., DM or IBM).

[0186] As used herein, the term “therapeutic agent” is intended to mean a compound that, when present in an effective amount, produces a desired therapeutic effect on a subject in need thereof.

[0187] “Treating” or “treatment” as used herein covers the treatment of a disease or disorder described herein, in a subject, such as a human, and includes: (i) inhibiting a disease or disorder, z.e., arresting its development; (ii) relieving a disease or disorder, z.e., causing regression of the disorder; (iii) slowing progression of the disorder; and / or (iv) inhibiting, relieving, or slowing progression of one or more symptoms of the disease or disorder. In some embodiments, treatment means that the symptoms associated with the disease are, e.g., alleviated, reduced, cured, or placed in a state of remission. In a further aspect, the term “treatment” excludes prevention or prophylactic use.

[0188] At various places in this disclosure, substituents of compounds provided herein are disclosed in groups or in ranges. It is specifically intended that these groups and ranges include each and every individual subcombination of the members of such groups and ranges.-170- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOFor example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.

[0189] At various places in this disclosure various aryl, heteroaryl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, pyri din-3 -yl, or pyridin-4-yl ring.

[0190] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution can be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency.

[0191] The term "alkyl", by itself or as part of another substituent, means, unless otherwise stated, a saturated monovalent hydrocarbon radical, having, in some embodiments, one to eight (e.g., Ci-Cs alkyl), or one to six (e.g., Ci-Ce alkyl), or one to three (e.g., C1-C3 alkyl) carbon atoms, respectively. The term “alkyl” encompasses straight and branched-chain hydrocarbon groups. Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, isopentyl, tert-pentyl, n-pentyl, isohexyl, n-hexyl, n-heptyl, 4-isopropylheptane, n-octyl, and the like. In some embodiments, the alkyl groups are C1-C4 alkyl groups (e.g., methyl, ethyl, isopropyl, or t-butyl). In some embodiments, the alkyl groups are C1-C3 alkyl groups (e.g., methyl, ethyl, n-propyl, or isopropyl).

[0192] As used herein, the term “alkoxy” refers to an alkyl group, as defined herein, that is attached to the remainder of the molecule via an oxygen atom (e.g., -O-C1-C12 alkyl, -O-Ci-Cx alkyl, -O-Ci-Ce alkyl, or -O-C1-C3 alkyl). Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and the like. In some embodiments, the alkoxy groups are C1-C3 alkoxy groups (e.g., methoxy, ethoxy, n-propoxy, or iso-propoxy).

[0193] As used herein, the term “amino” refers to a group of formula -NH2.-171- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0194] As used herein, the term “alkyl amino” refers to a group of formula -NH(alkyl). In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, without limitation, N-methylamino, N-ethylamino, N-propylamino (e.g., N-(propyl)amino and N-isopropylamino), N-butylamino (e.g., N-(butyl)amino and N-(-butyl)amino). and the like.

[0195] As used herein, the term “di(alkyl)amino” refers to a group of formula - N(alkyl)2. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0196] As used herein, “halo” or “halogen” means, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl" and “haloalkoxy” refer to alkyl groups and alkoxy groups, respectively, as defined herein, that are substituted with one or more halogen(s) (e.g., 1-3 halogen(s)). For example, the term " C1-C4 haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. As another example, the term “C1-C3 haloalkoxy” is meant to include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 2,2-difluoroethoxy, and the like.

[0197] The term "aryl" refers to an aromatic ring system containing one ring, or two or three rings fused together, and having, in some embodiments, six to fourteen (i.e., Ce-Cu aryl), or six to ten (i.e., Ce-Cio aryl), or six (i.e., Ce aryl) carbon atoms. Non-limiting examples of aryl groups include phenyl, naphthyl and anthracenyl. In some embodiments, aryl groups are phenyl.

[0198] The term "cycloalkyl" refers to a monocyclic, bicyclic or polycyclic hydrocarbon ring system having, in some embodiments, 3 to 14 carbon atoms (e.g., C3-C14 cycloalkyl), or 3 to 10 carbon atoms (e.g., C3-C10 cycloalkyl), or 3 to 8 carbon atoms (e.g., C3-C8 cycloalkyl), or 3 to 6 carbon atoms (e.g., C3-C6 cycloalkyl) or 3 to 4 carbon atoms (e.g., C3-C4 cycloalkyl). Cycloalkyl groups can be saturated or characterized by one or more points of unsaturation (i.e., carbon-carbon double and / or triple bonds), provided that the points of unsaturation do not result in an aromatic system. Examples of monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cyclooctyl, cyclooctenyl, cyclooctadienyl and the like. The-172- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOrings of bicyclic and polycyclic cycloalkyl groups can be fused, bridged, or spirocyclic. Nonlimiting examples of bicyclic, spirocyclic and polycyclic cycloalkyl groups include bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, adamantyl, indanyl, spiro[5.5]undecane, spiro[2.2]pentane, spiro[2.2]pentadiene, spiro[2.3]hexane, spiro[2.5]octane, spiro[2.2]pentadiene, and the like. In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic C3-C6 cycloalkyl moieties (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl). In some embodiments, the cycloalkyl groups of the present disclosure are monocyclic C3-C4 cycloalkyl moieties (e.g., cyclopropyl, or cyclobutyl).

[0199] The term "heteroaryl" refers to monocyclic or fused bicyclic aromatic groups (or rings) having, in some embodiments, from 5 to 14 (i.e., 5- to 14-membered heteroaryl), or from 5 to 10 (i.e., 5- to 10-membered heteroaryl), or from 5 to 6 (i.e., 5- to 6-membered heteroaryl) members (i.e., ring vertices), and containing from one to five, one to four, one to three, one to two or one heteroatom independently selected from nitrogen (N), oxygen (O), and sulfur (S). A heteroaryl group can be attached to the remainder of the molecule through a carbon atom or a heteroatom of the heteroaryl group, when chemically permissible. Nonlimiting examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, purinyl, thienopyridinyl, thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl, thiazolyl, furyl, thienyl and the like. In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6-membered heteroaryl moieties having 1-3 heteroatoms independently selected from N, O, and S (e.g., pyridinyl, pyrimidinyl, pyridazinyl, triazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, or thiazolyl). In some embodiments, the heteroaryl groups of the present disclosure are monocyclic 5- to 6-membered heteroaryl moieties having 1-2 ring nitrogen atoms (e.g., pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, or pyrazolyl).

[0200] The term "heterocycloalkyl" refers to a non-aromatic monocyclic, bicyclic or polycyclic cycloalkyl ring having, in some embodiments, 3 to 14 members (e.g., 3- to 14-membered heterocycle), or 3 to 10 members (e.g., 3- to 10-membered heterocycle), or 3 to 8 members (e.g., 3- to 8-membered heterocycle), or 3 to 6 members (e.g., 3- to 6-membered heterocycle), or 5 to 6 members (e.g., 5- to 6-membered heterocycle), and having from one to five, one to four, one to three, one to two or one heteroatom or heteroatom groups-173- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOindependently selected from nitrogen (N), oxygen (O), sulfur (S), sulfoxide (S(O)), and sulfone (S(O)2). Heterocycloalkyl groups are saturated or characterized by one or more points of unsaturation (e.g., one or more carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen double bonds, and / or nitrogen-nitrogen double bonds), provided that the points of unsaturation do not result in an aromatic system. The rings of bicyclic and polycyclic heterocycloalkyl groups can be fused, bridged, or spirocyclic. Non-limiting examples of heterocycloalkyl groups include aziridine, oxirane, thiirane, pyrrolidine, imidazolidine, pyrazolidine, di oxolane, phthalimide, piperidine, 1,4-di oxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, 3, 4,5,6-tetrahydropyridazine, tetrahydropyran, pyran, decahydroisoquinoline, 3-pyrroline, thiopyran, tetrahydrofuran, tetrahydrothiophene, tetrahydro-l, l-dioxido-27 / -thiopyran, quinuclidine, 1,4-oxazepane, 2-azabicyclo[4.1.0]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, 2-azabicyclo[2.2.1]heptane, 2,5-diazabicyclo[2.2.1]heptane, 6-oxa-3-azabicyclo[3.1.1]heptane, 3-oxa-6-azabicyclo[3.1. l]heptane, 2,5-diazabicyclo[2.2. l]heptane, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 2,6-diazaspiro[3.3]heptane, 2-azaspiro[3.3]heptane, 1-oxaspiro[3.3]heptane, 5-azaspiro[2.4]heptane, 6-azaspiro[3.4]octane, 6-azaspiro[2.5]octane, 4-oxa-7-azaspiro[2.5]octane, 3-oxa-8-azabicyclo[3.2.1]octane, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon atom, or a ring heteroatom, when chemically permissible. In some embodiments, the heterocycloalkyl groups of the present disclosure are monocyclic 4- to 8- membered heterocycloalkyl moieties having one or two heteroatom or heteroatom groups independently selected from N, O, S and S(O)2(e.g., azetidine, piperidine, piperazine, morpholine, pyrrolidine, imidazolidine, pyrazolidine, tetrahydrofuran, tetrahydropyran, 1,4-oxazepane, 6-oxa-3 -azabicyclo[3.1.1 ]heptane, 3 -oxa-6-azabicyclo[3.1.1 ]heptane, 2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, and the like).

[0201] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, any ringforming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring-174- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOmembers independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur, and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary five-membered ring heteroaryls include, without limitation, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1.2.3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4- oxadiazolyl, 1,3,4-triazolyl, 1.3.4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, and S. Exemplary six-membered ring hetero aryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. Ringforming carbon atoms of a heteroaryl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from O, N, or S. Included in heterocycloalkyl are monocyclic 4-, 5-, 6-, 7-, 8-, 9-, or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include, without limitation, pyrrolidin- 2-one, l,3-isoxazolidin-2-one, pyranyl, tetrahydropyran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(O), S(O), C(S), or S(O)2, etc.). The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moi eties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group-175- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOcontaining a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0202] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring can be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3 -position.

[0203] Various embodiments are described hereinafter. It should be noted that the specific embodiments are not intended as an exhaustive description or as a limitation to the broader aspects discussed herein. One aspect described in conjunction with a particular embodiment is not necessarily limited to that embodiment and can be practiced with any other embodiment(s).

[0204] The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.EXAMPLES

[0205] Example 1 - Non-Diseased Cells

[0206] The purpose of this example was to show that the POLg activators described herein do not improve mtDNA recovery in wild type normal human dermal fibroblasts (i.e., cells that are not characterized by MDDS).

[0207] WT-NHDF cells were obtained from PromoCell (C-12302). WT-NHDF were cultured in Dulbecco’s Modified Eagle Medium (DMEM; 4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 10% fetal bovine serum (FBS) at 37 °C in a 5% CO2 humidified cell incubator. mtDNA depletion in the WT-NHDF cells were induced by-176- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOadding 50 ng / mL ethidium bromide (EtBr) to the culture medium for up to 7 days, followed by returning the WT-NHDF cells to EtBr-free media. The POLg activator (l-((5 -8-chlorochroman-4-yl)-3- (2-(l-hydroxyethyl)thiazol-4- yl)urea, the S enantiomer (Cl)) was added at concentration of 1 pM, while vehicle (0.01% DMSO) served as a control.

[0208] The results shown in FIG. 2 demonstrate that the POLg activators of the present invention do not change the rate of mtDNA recovery in normal healthy wildtype cells not afflicted with a PMD, and particularly not affected with MDDS.

[0209] Example 2 - MDDS Characterized by MPV17, RRM2B, or DGUOK mutations

[0210] The purpose of this example was to evaluate the ability of POLg activators described herein to improve mtDNA recovery for MPV17, RRM2B, or DGUOK mutant fibroblasts. In these fibroblasts, the mtDNA replication machinery is fully functional (i.e., there is no POLg mutation). However, these cells with mutations in MPV17, RRM2B, or DGUOK exhibit low dNTP pool levels, which result in low mtDNA copy number despite a fully functional replisome. Primary fibroblasts were obtained from patients with a mutation in MPV17 (FIG.3A and FIG. 3D) carrying heterozygote mutations P64R / Y168C, a mutation in DGUOK (FIG. 3C) carrying a heterozygote of one missense mutation and one nonsense mutation R39G / F256*, or a mutation in RRM2B ( FIG. 3B) carrying a homozygote in-frame deletion, E85del / +. Fibroblasts were cultured in DMEM (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 10% at 37°C in a 5% CO2 humidified cell incubator. mtDNA depletion was induced by adding 50 ng / mL ethidium bromide (EtBr) to the culture medium for 7 days. On day 7, quiescence was induced by culturing the cells in EtBr-free DMEM (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 0.1% FBS. On day 10, the S, S stereoisomer of 1-((S)-8-chlorochroman-4-yl)-3-(2-((5)-l-hydroxyethyl)thiazol-4-yl)urea (Cl), the S, R stereoisomer of l-((5)-8-chlorochroman-4-yl)-3-(2-((A)-l -hydroxy ethyl)thiazol-4-yl)urea (C3), and (5)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(l-methyl-lH-pyrazol-3-yl)thiazol-4-yl)urea (C2) were added at concentrations of 0.1 or 1 pM, while vehicle (0.01% DMSO) served as a control. Compound treatment was performed for 7 or 14 days in a quiescent state, with media changes every 3-4 days. All conditions were performed in triplicates.-177- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0211] DNA samples were extracted from cell pellets with the Zymo kit and EZ-Vac Vacuum Manifold according to manufacturer’s protocol. Undiluted DNA samples were then digested with BamHI-HF (>10 U / pg DNA) at 37 °C for 15 min. Samples were diluted (at least 1:5) with nuclease-free water before qPCR. qPCR was performed in triplicate on a 384-well reaction plate. Each PCR reaction (final volume 10 pL) contained 1-10 ng DNA, lx SYBR Green PCR master mix, and 250 nM of forward and reverse primer each. mtDNA was amplified using primers specific to human CYTB gene in the mitochondrial genome, and B2M gene as nuclear gene reference. For quantitative assessment of qPCR data, a plasmid containing CYTB + B2M was used to generate a standard curve starting from 0.02 ng plasmid DNA and 15x 1:2 dilutions (Cq-value range: Cytb=13-30 and B2M=16-34). The mtDNA copy number was determined by using the following equation: (Copy of CYTB) *2 / (Copy of B2M). Data were analyzed using Brown-Forsythe and Welch one-way ANOVA for multiple comparisons where compound-treated groups were compared to the DMSO control using GraphPad Prism software version 10. All data were reported as the mean ± s.e.m. Significance was defined as P < 0.05. Asterisks represent corresponding statistical significance as follows: *P < 0.05, **P < 0.01 and ***P < 0.001 (Undepleted T7 = Nondepleted control in proliferation; EtBr T7= +EtBr = 7-day depletion sample; EtBr T7+3 = 7-day depletion plus 3 days in quiescence control sample).

[0212] Contrary to the conclusion drawn from the results in FIG. 2 where the POLg activators of the present invention had no significant effect on the improvement in mtDNA recovery in perfectly healthy WT-NHDF cells, FIG. 3A-D demonstrate that treatment with the POLg activators of the present invention accelerate mtDNA recovery relative to a control for mutant MPV17 (FIG. 3A and FIG 3D), mutant RRM2B (FIG. 3B) and mutant DGOUK (FIG. 3C) patient fibroblasts (e.g., accelerated mtDNA recovery relative to a control). This data demonstrates that the POLg activators of the present invention accelerate the recovery of mtDNA levels in MDDS not characterized by a POLG mutation.

[0213] Example 3 - MDDS Characterized by TWINKLE mutation

[0214] The purpose of this example was to evaluate the ability of the POLg activators described herein to increase mtDNA levels in the presence of mutations in the TWINKLE gene. Time-course experiments demonstrate that POLg activators of the present invention-178- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOincreased total mtDNA in the presence of various mutant TWINKLE variants during TWINKLE-dependent rolling-circle DNA replication. Wild-type or mutant TWINKLE variants were incubated with POLy and mtSSB, either in the absence (FIG. 4A) or presence (FIG. 4B) of 1 pM of a POLg activator of described herein, using a rolling-circle template at 37 °C for the indicated times. DNA synthesis was monitored by the incorporation of radioactive nucleotides, and the resulting DNA products of increasing length were resolved on a 0.8% alkaline agarose gel.

[0215] A double-stranded DNA template with a preformed replication fork was generated by annealing a 70-mer oligonucleotide (5'-T42ATC TCA GCG ATC TGT CTA TTT CGT TCA T-3') to single-stranded pBluescript SK(+) OL, followed by one cycle of polymerization with KOD polymerase. The template (0.4 nM) was added to a reaction mixture (final volume 25 pl) containing 25 mM HEPES-NaOH, pH 7.6, 10 mM DTT, 10 mM MgCl2, BSA (0.1 mg / ml), 1 mM ATP, 2 pCi of a-[32P] dCTP, 10 pM of all four dNTPs, 1% DMSO, 4 nM TWINKLE (wild-type or mutant variants, calculated as a hexamer), 160 nM mtSSB (calculated as a tetramer), 6 nM POLy A, and 9 nM POLyB (calculated as a dimer). 1 pM 1-[(4S)-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)urea (C5) was added to the reactions. After incubation at 37 °C for times indicated, reactions were terminated by adding 8 pl of alkaline loading buffer [18% (w / v) Ficoll, 300 nM NaOH, 60 mM EDTA pH 8.0, 0.25% (w / v) bromophenol blue, and 0.25% (w / v) xylene cyanol FF] and the reaction products were separated on a 0.8% denaturing agarose gel at 40 V for 20 hr. Reactions products were visualized by autoradiography (FIGs. 4A & B).

[0216] FIGs. 4A & B show that the compounds described herein increased mtDNA count in the presence of nuclear mutations that cause a form of MDDS (e.g., a TWINKLE mutation). FIG. 4A shows that mtDNA was not synthesized in the absence of the compound, except for in the presence of WT TWINKLE. FIG. 4B shows that in the presence of 1 pM of compound, full-length mtDNA was synthesized for each patient derived fibroblast TWINKLE mutant Q670H, K656Q, G540R, and E461K. FIG. 4B also shows that the amount of full-length mtDNA synthesized with WT POLG and WT TWINKLE increased in the presence of the compound. These data show that the POLg activators described herein increased total mtDNA in the presence of various mutant TWINKLE variants with wild-type-179- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOPOLD, and also increase mtDNA in the presence of WT TWINKLE and WT POLG, demonstrating that the compounds increase the activity of wild-type POLG.

[0217] Example 4 - MDDS Characterized by TK2 mutation

[0218] The purpose of this example was to evaluate the ability of POLg activators described herein to increase the mtDNA copy number in the presence of TK2 mutations that cause MDDS.

[0219] Primary fibroblasts were obtained from a patient with mutations in the TK2 gene carrying a homozygous p.fMetl Vai] mutation. The patient fibroblasts were cultured in DMEM (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 10% FBS at 37°C in a 5% CO2 humidified cell incubator. mtDNA depletion was induced by adding 50 ng / mL ethidium bromide (EtBr) to the culture medium for 7 days. On day 7, cells were cultured in EtBr-free DMEM media (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) and l-[(45)-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)urea was added at a concentration of 1 pM, while vehicle (0.01% DMSO) served as a control. DNA samples were extracted from cell pellets with the Zymo kit and EZ-Vac Vacuum Manifold according to manufacturer’s protocol. Undiluted DNA samples were then digested with BamHI-HF (>10 U / pg DNA) at 37 °C for 15 min. Samples were diluted (at least 1:5) with nuclease-free water before qPCR. qPCR was performed in triplicate on a 384-well reaction plate. Each PCR reaction (final volume 10 pL) contained 1-10 ng DNA, lx SYBR Green PCR master mix, and 250 nM of forward and reverse primer each. mtDNA was amplified using primers specific to human CYTB gene in the mitochondrial genome, and B2M gene as nuclear gene reference. For quantitative assessment of qPCR data, a plasmid containing CYTB + B2M was used to generate a standard curve starting from 0.02 ng plasmid DNA and 15x 1:2 dilutions (Cq-value range: Cytb=13-30 and B2M=16-34). The mtDNA copy number was determined by using the following equation: (Copy of CYTB) *2 / (Copy of B2M). Data were analyzed using Brown-Forsythe and Welch one-way ANOVA for multiple comparisons where compound-treated groups were compared to the DMSO control using GraphPad Prism software version 10. All data were reported as the mean ± s.e.m. Significance was defined as P < 0.05. Asterisks represent corresponding statistical significance as follows: *P < 0.05, **P < 0.01 and ***P < 0.001. FIG. 5 shows that POLg activators described herein increased-180- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOmtDNA copy number in the presence of TK2 mutations that cause MDDS after 7 and 14 days of treatment. In particular, FIG. 5 shows that the POLg activators increased mtDNA in TK2d patient fibroblasts (TK2 Ml V mutant fibroblasts. TK2 (thymidine kinase 2) deficiency leads to MDDS.

[0220] Example 5 - Animal Model of MDDS Characterized by DGUOK mutation

[0221] The purpose of this example was to evaluate the ability of POLg activators described herein to elicit positive pharmacology (e.g., improved liver health) in an MDDS model of knock-out DGUOK mice.

[0222] Two-month-old Homozygous DGUOK knockout mice [https: / / doi.org / 10.1093 / hmg / ddzl03] were orally administered the A'-enantiomer of l-((5 -8-chlorochroman-4-yl)-3- (2-(l-hydroxyethyl)thiazol-4- yl)urea (Cl) at 300 mg / kg / day for 28 days. These mice have a severe mtDNA depletion phenotype in the liver, with mtDNA levels only 3% of normal levels, accompanied by elevated circulating liver enzymes. After treatment with 300 mg / kg of the POLg activator, DGUOK-treated mice had significantly more liver mtDNA and lower liver enzymes than vehicle-treated DGUOK mice (measured by PCR of mtDNA gene CytB, and circulating ALT levels).

[0223] FIGs. 6A and B show that the POLg activators described herein elicit positive pharmacology (e.g., improved liver health) in a DGUOK-KO mice model. Although these mice have wild-type POLG, DGUOK-KO mice have depleted mtDNA due to low nucleotide (dNTP) availability. FIG. 6A (liver enzymes) and FIG. 6B (liver mtDNA) show that DGUOK-KO l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea-treated mice had improved liver health (following 28 days of treatment (oral QD)).

[0224] Example 6- Animal Model of MDDS Characterized by TK2 mutations

[0225] The purpose of this example was to evaluate the ability of POLg activators described herein to elicit positive pharmacology (e.g., improved life span) in a TK2 mutation mouse model of MDDS. In this model, knockout of TK2 (TK2-KO) elicits low dNTP availability and mtDNA is severely depleted. Although these mice have wild-type POLG, the severe mtDNA depletion leads to a decrease in survival (TK2-KO mice have a median survival of 17 days). TK2-KO mice were administered a daily oral dose of either l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea (C3) (100 mg / kg in Esbilac -181- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOmilk, n=6 male, n=4 female) or vehicle (Esbilac milk, n=6 male, n=5 female) beginning on Day 4 of life. FIG. 7A shows treatment with the POLg activator led to a 47% increase in median survival compared to vehicle-treated mice.

[0226] In a separate cohort of mice, under identical experimental conditions, liver mtDNA copy number was determined by quantitative PCR. TK2-KO mice treated with 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea (C3) (100 mg / kg, n=4 female, n=6 male) had significantly higher liver mtDNA copy number than TK2 KO mice treated with vehicle (Esbilac milk, n=8 female, n=2 male) as shown in FIG. 7B. Wildtype mice were also analyzed and had higher levels of liver mtDNA copy number than both TK2-KO groups.

[0227] Example 7 - Clinical Trial

[0228] This example describes a proposed Phase 2, Open-label, Multiple Dose Study of the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea (C3) in Patients with Primary Mitochondrial Disease That is Not Associated with Pathogenic POLG Mutations.

[0229] Enrollment: Adolescent / adult patients with primary mitochondrial disease that is not associated with mutations in the DNA polymerase y gene.

[0230] Objectives:

[0231] Safety- to assess the safety and tolerability of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea (hereinafter “Study Drug”) at two pharmacologically active dose levels. Endpoints: (i) Frequency of treatment-emergent adverse events (TEAE); (ii) Frequency of treatment-emergent, clinically-significant changes in physical examination, vital signs, ECG or safety laboratory assessments.

[0232] Pharmacokinetics - to assess two dose pharmacokinetics (PK) of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea in the plasma of patients with Primary Mitochondrial Disease That is Not Associated with Pathogenic POLG Mutations. Endpoints: (i) Measured plasma concentration of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea (C3); (ii) Plasma PK parameters including but not limited to Tmax, Cmax, volume of distribution, area under the curve (AUC) and T1 / 2.-182- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0233] Pharmacodynamics- to assess the effects of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea (C3) on plasma biomarkers related to abnormal mitochondrial function associated with symptomatic disease presentation. In addition, in patients presenting with lower limb myopathy, to assess the effects of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea on mtDNA copy number in skeletal muscle. Endpoints: (i) In all subjects, change from baseline in circulating markers of mitochondrial function (e.g. lactate, GDF-15 andFGF-21); (ii) Subjects presenting with lower limb myopathy: change from baseline in creatinine phosphokinase (CPK) as marker of muscle injury. Change from baseline in muscle mtDNA copy number as measured by PCR in muscle biopsy sample; and (iii) Subjects presenting with central nervous system disease manifestation (e.g. ataxia, neuropathy, epilepsy, etc): change from baseline in circulating markers of neuronal and blood brain barrier health (NFL, albumin, etc.).

[0234] Exploratory Objectives: (1) To assess the effects of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea on exploratory biomarkers related to abnormal mitochondrial function associated with symptomatic disease presentation. In addition, to explore the effects of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea on disease symptoms.

[0235] Endpoints

[0236] In subjects presenting with primary complaint of central nervous system (CNS) disease manifestation (eg, ataxia, neuropathy, epilepsy, etc): change from baseline in circulating markers of neuronal and blood brain barrier health (neurofilament light chain [NfL], albumin, etc).

[0237] Change from baseline in exploratory biomarkers related to mitochondrial disease including but not limited to circulating cell-free mtDNA.

[0238] Change from baseline in clinical assessments of myopathy including but not limited to 6Minute Walk Test (6MWT), fatigue score, Newcastle Mitochondrial Disease Adult Scale (NMDAS), QoL patient reporting, Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC).

[0239] Change from baseline in sensorineural hearing.-183- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0240] Change from baseline in clinical / EEG assessments of neuropathology (ataxia scale such as International Cooperative Ataxia Rating Scale (ICARS) or the Scale for the Assessment and Rating of Ataxia.

[0241] Change from baseline electromyography (EMG).

[0242] Study Design: Study Drug is a novel, orally administered small molecule that is anticipated to increase mtDNA copy number in cells with mtDNA depletion via activation of the mtDNA polymerase (POLy). This Phase 2 first-in-patient study incorporates a dose escalation and an age de-escalation design. Based on preclinical results and dose modeling, two Study Drug dose levels will be tested with twice daily dosing for 12 weeks. Subjects will then be offered the opportunity to continue Study Drug dosing in the open-label extension (OLE) part of the trial for up to 1 yr of total dosing or alternatively, to proceed to post-dosing PK assessment and safety monitoring during the 4-week follow-up period. Both males and females will be eligible to participate. Subjects in the OLE will continue on the same dose they were taking in the core study. When all subjects have completed the 3 month core treatment period and the Safety Review Committee (SRC) have reviewed the data, subjects in the low dose group may be allowed to increase the dose for the remainder of the OLE.

[0243] For each cohort, potential subjects will be screened for a maximum of 28 days (Day -28) prior to Baseline (Day -1) to assess their eligibility to enter the study. Key screening activities will include confirmation of clinical diagnosis and pathogenic genetic mutation(s), documentation of blood markers of mitochondrial dysfunction (two values, at least 14 days apart), and in subjects presenting with lower-limb myopathy, a single muscle biopsy for assessing muscle mtDNA copy number prior to intervention.

[0244] Subjects will be admitted to the clinical unit on Day -1 for pre-dosing testing as described in the Schedule of Assessments (SoA) for the core treatment period (Table 1). Each dosing cohort will initiate with a sentinel subject. Following the sentinel subject, no more than 2 subjects will start dosing on the same day. On the morning of Day 1, all subjects will receive a single test dose of Study Drug (low- or high-dose depending on their cohort).Assuming Day 1 dosing is well tolerated, subjects will begin twice daily dosing on Day 2 while remaining at the clinical site for safety monitoring and collection of blood samples for PK analysis, safety assessments, PD markers, and exploratory analyses. Assuming there are-184- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOno clinically-concerning adverse events as determined by the site Investigator, subjects will be discharged following the morning dose on Day 3 (the duration of the clinic stay may be extended if there is a safety concern). Subjects will take their second dose on Day 3 at home and will continue with twice daily dosing at home.

[0245] On Day 84, subjects will be readmitted to the clinic and their last dose of Study Drug will be administered on Day 85 while they are in the clinic (a total 12 weeks of treatment including the test dose). Upon admission to the clinic on Day 84, subjects can choose to:

[0246] Stop Study Drug dosing at the end of the core treatment period on the morning of Day 85 and proceed to the 4-week Follow-Up Period for post-dosing PK assessment and monitoring, or enter the open-label extension (OLE) period and continue twice daily Study Drug dosing for a further 9 months (a total duration of up to 1 year [Day 366]).

[0247] Subjects who decide to stop Study Drug at the end of the core treatment period will remain at the clinical site for collection of blood samples for PK analysis, safety assessments, PD markers, exploratory endpoints and clinical assessments specific to each group and will be discharged from the clinic on Day 87. Following the Day 87 discharge, there will be 2 post-dosing visits, scheduled 2 weeks and 4 weeks after the last Study Drug dose to monitor safety and duration of effect. These visits will include clinical, safety and PD assessments as outlined in the SoA. The end of study (EOS) visit will be at Day 113; note that if a subject elects to stop dosing at Day 85, this will not be considered early termination.

[0248] If the subject elects to continue in the OLE, they will remain at the clinical site from Day 84 through D86 for collection of blood samples for PK analysis, while continuing on the same dose and dosing frequency as for the core dosing period. Following discharge from the clinic on Day 87, subjects will continue taking Study Drug twice daily at home and will return to the clinic initially every month and then every 3 months.

[0249] On Day 365, subjects will be readmitted to the clinic for collection of blood samples for PK analysis, safety assessments, PD markers, exploratory endpoints and clinical assessments specific to each group. The last dose of Study Drug will be administered on Day 366 while they are in the clinic. Subjects will be discharged from the clinic on Day 368. Following discharge from the clinic there will be 2 post-dosing visits, scheduled 2 weeks and -185- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO4 weeks after the last Study Drug dose to monitor safety and duration of effect. These visits will include clinical, safety and PD assessments as outlined in the SoA. The EOS visit will be at Day 394.

[0250] Note that if a subject discontinues from study dosing at any point during the core 12 week period or during the 9 month OLE they should be followed for safety and PD assessments at 2 weeks and 4 weeks post last dose as described above.

[0251] Dose-escalation strategy

[0252] The cohort study design incorporates a dose escalation and an age de-escalation strategy as shown in the Study Schema. This is initiated with an adult only, low dose cohort (Cohort 1). Following SRC review, and if no safety signals are detected then Cohort 2 (adults, high-dose) and Cohort 3 (age de-escalation: adolescents, aged 12-17 years; low-dose) will be initiated in parallel. Following SRC review of safety data for Cohort 2 and Cohort 3, the final high dose cohort (Cohort 4) of adolescents aged 12-17 years will be initiated.

[0253] Cohort enrollment and data for dose-escalation

[0254] Each dosing cohort will initiate with a sentinel subject. Assuming no subject stopping rules (see below) are met through Day 8 (7 days of daily dosing), the remainder of the cohort may be enrolled (2-4 additional subjects, with no more than 2 subjects dosed on the same day). Dose-escalation (Cohort 2) and age de-escalation (Cohort 3) decisions by the SRC will be confirmed following review of all safety / tolerability data and any available PK data from at least 3 subjects per cohort over at least 14 days of dosing.

[0255] Study Drug Dose

[0256] There will be two dose levels (low- and high-dose) in this study. Biochemical and pharmacological data alongside a quantitative systems pharmacology (QSP) model will be used to propose the doses. The low dose of Study Drug is expected to result in partial maximal POLG activation. The high dose of Study Drug is expected to achieve maximal POLG activation. Neither dose will exceed the highest dose previously administered and-186- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOshown to be safe and well-tolerated in the Phase 1 adult healthy volunteer single / multiple ascending dose study conducted ex-US.

[0257] Safety Review Committee (SRC)

[0258] The SRC will consist of the study Medical Monitor (MM), Principal Investigator (PI), and Sponsor Chief Medical Officer or designee. A detailed description of SRC composition, roles, responsibilities, and meeting schedules is provided in a separate SRC charter maintained by the Sponsor. The SRC will review study subject safety data throughout the trial as described in the SRC charter, and provided no safety concerns are identified, may issue a non-objection to continue the trial as planned.

[0259] Subject Stopping Rules

[0260] At a minimum, dosing will be stopped for an individual subject for any of the following:

[0261] Any serious adverse event (SAE) or any Grade 3 or higher AE (by Common Terminology Criteria for Adverse Events [CTCAE] v5.0 criteria): Pregnancy, Withdrawal of consent, Non-compliance or safety finding during the study conduct such that PI considers continued participation to put the subject at increased risk, having the following liver function test abnormalities at any time after dosing: Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper limit of normal (ULN), ALT or AST > 3 x ULN in conjunction with elevated total bilirubin > 2 x ULN or international normalized ratio (INR) > 1.5, ALT or AST > 3 x ULN with appearance of fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and / or eosinophilia, Conjugated bilirubin > 1.5 x ULN in absence of Gilbert Syndrome diagnosis, Non-compliance or safety finding during the study conduct such that PI considers continued participation to put the subject at increased risk, Serum creatinine > 1.5 x ULN, Mean QTcF > 500 msec or > 60 msec change from baseline, Any clinically relevant allergic reaction / hypersensitivity (e.g., fever > 39°C, dyspnea), Clinically-significant protocol deviation affecting subject safety-187- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0262] In the setting of a subject meeting stopping rules, an ad hoc SRC review will be constituted to determine appropriate next steps including whether dosing can be restarted. If restarted it will be at the dose level originally assigned.Cohort Suspension Rules

[0263] Dosing will be stopped for all subjects in a given cohort such that subsequent subjects in the cohort cannot be given the same or a higher dose, if any of the following occur (at a minimum) and are considered study drug related by the PI: Any 2 subjects with SAEs or severe (Grade 3 or higher) AEs in the same system organ class (SOC) based on CTCAE v5.0 criteria, Any 2 subjects with AEs of Grade 2 or less in the same SOC based on CTCAE v5.0 criteria which in the opinion of the Principal Investigator require further evaluation to determine progression risk, Any 2 subjects with ALT and / or AST > 5 x ULN in the absence of a concomitant bilirubin increase, with no alternative etiology to explain the elevations, Any subject with ALT and / or AST > 3 x ULN in the presence of a total bilirubin increase >2 x ULN or an INR > 1.5 without findings of cholestasis or other alternative etiology to explain the elevations, Any subject with ALT and / or AST elevations > 3 x ULN with new onset fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and / or eosinophilia, with no alternative etiology to explain the elevations. Any 2 subjects with serum creatinine > 1.5 x ULN, Any 2 subjects with mean QTcF > 500 msec or > 60 msec change from baseline, Any 2 subjects with clinically relevant allergic reach on / hypersensitivity (e.g., fever > 39°C, dyspnea).

[0264] In the setting of a cohort dosing pause, the SRC will review all available safety-related data in determining whether dosing should be paused in other cohorts and when / if dosing can be resumed. SRC decisions will be documented for the trial master file and submitted to local / country ethics and regulatory authorities prior to restarting dosing.-188- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOExample 8- Synthesis of l-((5)-8-chlorochroman-4-yl)-3-(2-(l-hydroxyethyl)thiazol-4-yl)ureaKEStep 4 Step-2 14 141 fi

[0265] Step-1: l-[(4S)-8-chlorochroman-4-yl]-3-[2-(l-ethoxyvinyl)thiazol-4-yl]urea (1-3)'. To a stirred solution of l-(2-bromothiazol-4-yl)-3-[(45)-8-chlorochroman-4-yl]urea 1-1 (0.50 g, 1.29 mmol) in 1,4-dioxane (10 mL) was added tributyl(l-ethoxyvinyl)tin 1-2 (0.53 mL, 1.54 mmol) followed by KF (0.22 g, 3.86 mmol) at RT. The reaction mixture was purged with nitrogen for 15 min and then Z> A(triphenylphosphine)palladium (II) chloride (0.09 g, 0.12 mmol) was added into it. The reaction mixture was heated at 110 °C for 6 h. After completion, reaction mixture was filtered through Celite bed. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The product was purified by CombiFlash (20% EtOAc / heptane) to afford l-[(45)-8-chlorochroman-4-yl]-3 -[2-(l -ethoxy vinyl)thiazol-4-yl]urea 1-3 (0.35 g). 'H NMR (400 MHz, DMSO-d6) 6 = 9.22 (s, 1H), 7.32 (d, J= 7.9 Hz, 1H), 7.26 - 7.20 (m, 2H), 6.90 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 5.07 (s, 1H), 4.98 - 4.90 (m, 1H), 4.44 (br s, 1H), 4.41 - 4.36 (m, 1H), 4.28 -4.19 (m, 1H), 3.96 (q, J = 6.9 Hz, 2H), 2.13 (dd, J = 5.1, 8.3 Hz, 1H), 2.03 - 1.94 (m, 1H), 1.32 (t, J = 6.9 Hz, 3H); LCMS:[M+H]+= 380.-189- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0266] Step-2: l-(2-acetylthiazol-4-yl)-3-[(4S)-8-chlorochroman-4-yl]urea (1-4): To a stirred solution of l-[(45)-8-chlorochroman-4-yl]-3-[2-(l-ethoxyvinyl)thiazol-4-yl]urea 1-3 (0.35 g, 0.82 mmol) in acetone (5 mL) was added concentrated HC1 (1.00 mL, 33.30 mmol). Reaction mixture was stirred at RT for 1 h. After completion, reaction mixture was quenched with saturated NaHCCh solution, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford l-(2-acetylthiazol-4-yl)-3-[(45)-8-chlorochroman-4-yl]urea 1-4 (0.30 g) 'H NMR. (400 MHz, DMSO-d6) 6 = 9.48 (br s, 1H), 7.71 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 6.91 (t, J = 7.6 Hz, 1H), 6.82 (d, J = 7.9 Hz, 1H), 4.96 (d, J = 5.5 Hz, 1H), 4.38 (d, J = 7.9 Hz, 1H), 4.24 (t, J = 8.8 Hz, 1H), 2.57 (s, 3H), 2.12 (br s, 1H), 1.98 (br s, 1H);LCMS:[M+H]+= 352.

[0267] Step-3: l-[(4S)-8-chlorochroman-4-yl]-3-[2-(l-hydroxyethyl)thiazol-4-yl]urea (1-5): To a stirred solution of l-(2-acetylthiazol-4-yl)-3-[(45)-8-chlorochroman-4-yl]urea 1-4 (0.30 g, 0.76 mmol) in ethanol (8 mL) was added NaBH4 (0.13 g, 3.45 mmol) at 0 °C and the reaction mixture was stirred at 40 °C for 4 h. After completion, reaction mixture was concentrated under reduced pressure and product was quenched with H2O, extracted with EtOAc. Organic layer was washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure. Product obtained was purified by reverse phase CombiFlash to afford l-[(45)-8-chlorochroman-4-yl]-3-[2-(l-hydroxyethyl)thiazol-4-yl]urea 1-5 (0.13 g). LCMS:[M+H]+=354.

[0268] Step-4: l-((S)-8-chlorochroman-4-yl)-3-(2-(l-hydroxyethyl)thiazol-4-yl)urea (C3 and Cl): Diastereomeric mixture 1-5 l-[(45)-8-chlorochroman-4-yl]-3-[2-(l-hydroxyethyl)thiazol-4-yl]urea (0.13 g) was submitted for chiral -HPLC separation to afford C3 (0.04 g) and Cl (0.01 g).

[0269] C3: 'HNMR (400 MHz, DMSO-d6) 6 = 9.01 (s, 1H), 7.32 (dd, J= 1.3, 7.9 Hz, 1H), 7.25 - 7.20 (m, 1H), 7.05 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.02 (d, J = 5.3 Hz, 1H), 4.98 - 4.90 (m, 1H), 4.89 - 4.80 (m, 1H), 4.43 - 4.33 (m, 1H), 4.28 - 4.20 (m, 1H), 2.17 - 2.09 (m, 1H), 2.05 - 1.92 (m, 1H), 1.40 (d, J= 6.4 Hz, 3H); LCMS: [M+H]+=354.-190- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0270] Cl: 'HNMR (400 MHz, DMSO-d6) 6 = 9.00 (s, 1H), 7.32 (dd, J= 1.3, 7.9 Hz, 1H), 7.23 (d, J = 7 A Hz, 1H), 7.05 (s, 1H), 6.90 (t, J = 7.8 Hz, 1H), 6.81 (d, J = 7.9 Hz, 1H), 6.01 (d, J = 5.3 Hz, 1H), 4.97 - 4.90 (m, 1H), 4.89 - 4.80 (m, 1H), 4.44 - 4.35 (m, 1H), 4.29 - 4.18 (m, 1H), 2.19 - 2.05 (m, 1H), 2.03 - 1.93 (m, 1H), 1.40 (d, J = 6.5 Hz, 3H); LCMS: [M+H]+=354.Example 9- Synthesis of (S)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(l-methyl-lH-pyrazol-3-yl)thiazol-4-yl)ureaSte-p-i

[0271] Step-1: (S)-l-(8-chloro-3, 4-dihydro-2H-pyrano[ 3, 2-b ]pyridin-4-yl)-3-(2-( 1 -methyl-lH-pyrazol-3-yl)thiazol-4-yl)urea (C2): To the stirred solution of l-(2-bromothiazol-4-yl)-3-[(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]urea (38-5, 50 mg, 0.128 mmol) in 1,4-Dioxane (5 mL) and Water (0.5 mL) were added (l-methylpyrazol-3-yl)boronic acid (68-2, 24 mg, 0.192 mmol) followed by K3PO4 (82 mg, 0.385 mmol) and degassed under argon atmosphere for 20 min. Then Pd 118 (8.4 mg, 0.0128 mmol) was added and the reaction was stirred at 80 °C for 3 h. Reaction mixture was filtered through celite bed, diluted with water and extracted with ethyl acetate. Organic extract was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure to get crude. The product was purified by combi column chromatography to afford (S)-l-(8-chl oro-3, 4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(l-methyl-lH-pyrazol-3-yl)thiazol-4-yl)urea (C2, 30 mg). LCMS (ESI) cal cd. for C16H15CIN6O2S: 390.07, found [M+H]+: 391.2. HPLC: Rt(min) =6.65 (99.15 %). 'HNMR (400 MHz, DMSO-d6): 6H 9.41 (s, 1H), 8.10 (d, 1H), 7.81 (s, 1H), 7.47 (d, 1H), 7.09 (s, 1H), 6.94 (d, 1H), 6.61 (s, 1H), 4.92 (d, 1H), 4.44 (t, 1H), 4.33 (t, 1H), 3.89 (s, 3H), 2.35-2.20 (m, 1H), 2.08-1.98 (m, 1H).-191- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOExample 10- Synthesis of (S)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)- 3-(2-(l-cyclopropyl-lH-imidazol-4-yl)thiazol-4-yl)urea

[0272] Step-1: Synthesis of l-cyclopropyl-4-iodo-lH-imidazole: To a solution 4-iodo-lH-imidazole (38-1, 5 g, 25.8 mmol) in DCE (150 mL) were added 2-(2-pyridyl)pyridine (4.0 g, 25.8 mmol), Cu(OAc)2 (4.7 g, 25.8 mmol), cyclopropylboronic acid (38-2, 3.8 g, 43.8 mmol) and K2CO3 (7.1 g, 51.6 mmol) and stirred at ambient temperature for 24 h. The reaction mixture was filtered. Filtrate was concentrated and partitioned between water and EtOAc. The organic layer was collected and washed with a solution of 20% Q1SO4 in water, 10% aqueous NaOH and finally with brine. The organic layer was separated and dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude product was purified by combiflash to afford (l-cyclopropyl-4-iodo-lH-imidazole (38-3, 2.4 g). LCMS Calcd. for C6H7IN2: 234.04, found [M+H]+: 234.92. 'H NMR (400 MHz, CDCI3): 6H 7.56 (s, 1H), 7.05 (s, 1H), 3.37-3.32 (m, 1H), 1.01-0.91 (m, 4H). Formation of desired product was confirmed by NOE analysis.[0273 j Step-2: Synthesis of l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-IH-imidazole: To a stirred solution of l-cyclopropyl-4-iodo-lH-imidazole (38-3, 500 mg, 2.14 mmol) in 1,4-dioxane (15 mL) was added dry KOAc (629 mg, 6.41 mmol), bis(pinacolato)diboron (2.2 g, 8.55 mmol) and the reaction mixture was degassed with argon for 10 min. Pd(dppf)C12 (313 mg, 0.43 mmol) was added to the reaction mixture and stirred at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through-192- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOcelite bed and washed with EtOAc. The filtrate was evaporated under reduced pressure to afford l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-imidazole (38-4, 1 g). Used this crude compound for forwarding step without purification. LCMS Calcd. for C12H19BN2O2: 234.1, found [M+H]+: 234.95.

[0274] Step-3: Synthesis of (S)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(l-cyclopropyl-lH-imidazol-4-yl)thiazol-4-yl)urea (C4): A suspension of (S)-l-(2-bromothiazol-4-yl)-3-(8-chl oro-3, 4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 2.5 g, 6.42 mmol) and l-cyclopropyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)imidazole (38-4, 7.5 g, 16.0 mmol) in 1,4-dioxane (100 mL) and water (10 mL) was degassed with nitrogen and added K3PO4 (3.75 g, 7.7 mmol) and Pd(dppf)C12 CH2CI2 (524 mg, 0.64 mmol) at ambient temperature. The reaction mixture was heated at 100 °C for 7 h. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by combiflash chromatography followed by prep HPLC and lyophilized to afford (S)-l-(8-chl oro-3, 4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(l- cyclopropyl-lH-imidazol-4-yl)thiazol-4-yl)urea (C4, 418.55 mg). LCMS: Calcd. for C17H17CIN4O3: 416.88, found [M+H]+: 417.2. 'H NMR (400 MHz, DMSO-d6): 6n9.22 (s, 1H), 8.11-8.10 (d, 1H), 7.80 (d, 1H), 7.58 (d, 1H), 7.48-7.47 (d, 1H), 7.06-7.05 (d, 1H), 7.00 (s, 1H), 4.92-4.90 (m, 1H), 4.44-4.42 (m, 1H), 4.35-4.30 (m, 1H), 3.58-3.54 (m, 1H), 2.39-2.35 (m, 1H), 2.09-2.06 (m, 1H), 1.02-0.95 (m, 4H).Example 11- Synthesis of l-[(4 )-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)ureacarbonate DIFEA.rvrirsn? C H-. C r- H-N \ M 1IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0275] Step-1: Synthesis of l-[(4S)-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)urea: To a stirred solution of l-phenylpyrazol-3 -amine 34-1 (0.10 g, 0.63 mmol) in MeCN (3 mL) was added pyridine (0.05 g, 0.69 mmol) followed by bis(2,5-dioxopyrrolidin-l-yl) carbonate (0.16 g, 0.63 mmol). The resulting mixture was stirred at RT for 30 min. To this was added (45)-8-chlorochroman-4-amine 34-2 (0.12 g, 0.69 mmol) followed by DIPEA (0.16 mL, 0.94 mmol) and the reaction was stirred at 30 °C for 1 h. After completion, the reaction mixture was concentrated under reduced pressure and the product obtained was dissolved in ethyl acetate. The organic layer was washed with water, brine solution, dried over anhydrous Na2SC>4 and concentrated under reduced pressure. The product obtained was purified by prep HPLC to afford C5 (0.12 g). 'H NMR (400 MHz, DMSO-d6) 8 = 9.01 (s, 1H), 8.35 (d, 1H), 7.66 (dd, 2H), 7.46 - 7.40 (m, 2H), 7.34 (dd, 1H), 7.27 (dd, 1H), 7.24 - 7.13 (m, 2H), 6.92 (t, 1H), 6.51 (d, 1H), 5.00 - 4.92 (m, 1H), 4.45 - 4.36 (m, 1H), 4.31 - 4.20 (m, 1H), 2.22 - 2.11 (m, 1H), 2.09 - 1.98 (m, 1H); LCMS: [M+H]+= 369.Example 12- Synthesis of l-((S)-l-cyclopropylethyl)-3-(l-(4-((S)-2,2,2-trifluoro-l- hydroxyethyl)phenyl)-lH-pyrazol-3-yl)urea

[0276] Step-1: Synthesis of tert-butyl (S)-3-(3-(l-cyclopropylethyl)ureido)-lH-pyrazole-l- carboxylate: To a stirred solution of tert-butyl 3-amino-lH-pyrazole-l-carboxylate (98-1, 10 g, 54.6 mmol) in dichloromethane (800 mL) was added triphosgene (9.7 g, 32.7 mmol) followed by tri ethylamine (29 mL, 218 mmol) at -15 °C and stirred for 30 min at same condition. (S)-l-cyclopropylethan-l -amine (98-2, 5.1 mL, 54.6 mmol) was added under same condition and allowed to stir for 3 h at ambient temperature. The reaction mixture was diluted-194- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOwith dichloromethane and washed with water followed by brine solution. The organic layer was separated, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography to afford tert-butyl (S)-3-(3-(l-cyclopropylethyl)ureido)-lH-pyrazole-l-carboxylate (98-3, 11 g). LCMS (ESI) Cal cd. For C14H22N4O3: 294.2, found [M+H]+= 295.3. 'HNMR (400 MHz, DMSO-d6) 611: 9.19 (s, 1H), 8.06 (d, 1H), 6.72 (d, 1H), 6.46 (d, 1H), 3.31-3.22 (m, 1H), 1.54 (s, 9H), 1.12 (d, 3H), 0.88-0.83 (m, 1H), 0.43-0.36 (m, 2H), 0.30-0.25 (m, 1H), 0.10 (m, 1H).

[0277] Step-2: Synthesis of (S)-l-(l-cyclopropylethyl)-3-(lH-pyrazol-3-yl)urea: To a solution of tert-butyl (S)-3-(3-(l-cyclopropylethyl)ureido)-lH-pyrazole-l-carboxylate (98-3, 16 g, 54.4 mmol) in dichloromethane (150 mL) was added trifluoroacetic acid (42 mL, 544 mmol) drop wise at ice cold condition and stirred at ambient temperature for 4h. Volatiles were evaporated under reduced pressure. The crude product was dissolved in Ethyl acetate and washed with saturated aqueous NaHCCh solution (twice). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford (S)-l-(l-cyclopropylethyl)-3-(lH-pyrazol-3-yl) urea (98-4, 9.5 g). LCMS (ESI) Calcd. For C9H14N4O: 194.12, found [M+H]+= 195.2. 'HNMR (400 MHz, DMSO-d6) bH: 12.08 (bs, 1H), 8.59 (s, 1H), 7.51 (s, 1H), 6.9 (bs, 1H), 6.0 (s, 1H), 3.27-3.21 (m, 1H), 1.18 (d, 3H), 0.87-0.81 (m, 1H), 0.46-0.36 (m, 2H), 0.25 (m, 1H), 0.10 (m, 1H).

[0278] Step-3: Synthesis of l-((S)-l-cyclopropylethyl)-3-(l-(4-((S)-2,2,2-trifluoro-l-hydroxyethyl)phenyl)-lH-pyrazol-3-yl)urea (C7): To a solution of (S)-l-(l-cyclopropylethyl)-3-(lH-pyrazol-3-yl)urea (98-4, 3.56 g, 18.3 mmol) and (S)-l-(4-bromophenyl)-2,2,2-trifluoroethan-l-ol (98-5, 5.14 g, 20.2 mmol) in acetonitrile (140 mL) was added dried potassium carbonate (6.3 g, 45.8 mmol) at ambient temperature. The reaction mixture was degassed with argon for 10 min followed by the addition of trans-7V, V-dimethylcyclohexane-l,2-diamine (2.9 mL, 18.3 mmol) and Cui (1.7 g, 9.2 mmol). The reaction mixture was heated in a sealed tube at 90 °C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite bed and the bed was washed with ethyl acetate (twice). The combined filtrate was concentrated under reduced pressure. The crude product was purified by combi flash chromatography followed by trituration with 20% EtOAc in n-pentane to afford l-((S)-l-cyclopropylethyl)-3-(l-(4-((S)-2,2,2-trifluoro-l--195- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOhydroxyethyl)phenyl)-lH-pyrazol-3-yl)urea (C7, 2.5 g). LCMS (ESI) Calcd. For C17H19F3N4O2: 368.1, found [M+H]+: 369.2. 'HNMR (400 MHz, DMSO-d6) 6H: 8.96 (s, 1H), 8.34-8.33 (m, 1H), 7.75-7.73 (m, 2H), 7.57-7.55 (m, 2H), 6.86-6.85 (m, 1H), 6.68-6.66 (m, 1H), 6.44 (s, 1H), 5.20-5.15 (m, 1H), 3.28-3.23 (m, 1H), 1.16-1.14 (m, 3H), 0.92-0.86 (m, 1H), 0.47-0.36 (m, 2H), 0.29-0.25 (m, 2H).Example 13 - Synthesis of (S)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(pyridin-2-yl)thiazol-4-yl)urea

[0279] Step-1: Synthesis of (S)-l-(8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(pyridin-2-yl)thiazol-4-yl)urea (C8): To a stirred solution of (5)-l-(2-bromothiazol-4-yl)-3-(8-chl oro-3, 4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)urea (38-5, 150 mg, 0.4 mmol) in DMF (4 mL), LiCl (5 mg, 0.08 mmol) was added and degassed with nitrogen for 15 min. After 15 min. Cui (15 mg, 0.08 mmol), 2-(tributylstannyl)pyridine (59-2, 420 mg, 1.2 mmol), Pd(PPhs)4 (45 mg, 0.04 mmol) were added and continued stirring at 100 °C for 8 h. The reaction mixture was diluted with ethyl acetate and filtered through celite bed. The filtrate was washed with ice cold brine solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The product was purified by reverse phase preparative HPLC to afford (S)-l-(8-chl oro-3, 4-dihydro-2J / -pyrano[3,2-Z>]pyridin-4-yl)-3-(2-(pyri din-2 -yl)thiazol-4-yl)urea (C8, 65 mg). LCMS (ESI) Calcd. for C17H14CIN5O2S: 387.0, found [M+H]+= 388.1. 'HNMR (400 MHz, DMSO-t / 6): bn 9.48 (s, 1H), 8.62 (d, 1H), 8.12 (d, 1H), 8.01-7.93 (m, 2H), 7.49-7.46 (m, 2H), 7.32 (s, 1H), 7.08 (d, 1H), 4.95-4.93 (m, 1H), 4.45-4.43 (m, 1H), 4.37-4.35 (m, 1H), 2.40-2.32 (m, 1H), 2.10-2.07 (m, 1H).IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOExample 14 - Synthesis of l-((S)-l-cyclopropylethyl)-3-(l-(4-(l,l,l-trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea, & l-((S)-l-cyclopropylethyl)-3-(l-(4-(l,l,l-trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea

[0280] Step-1: Synthesis of l-((S)-l-cyclopropylethyl)-3-(l-(4-(l,1, 1 -trifluor o-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea: To a stirred solution of (S)-l-(l -cyclopropylethyl)-3-(lH-pyrazol-3-yl)urea (2-1, 200 mg, 1.0 mmol) and 2-(4-bromophenyl)-l,l,l-trifluoropropan-2-ol (2-2, 305 mg, 1.1 mmol) in acetonitrile (8 mL) was added oven dried K2CO3 (294 mg, 2.1 mmol) at ambient temperature and the reaction mixture was degassed with argon for 10 min. Copper(I) iodide (81 mg, 0.4 mmol) followed by trans-N, N'-dimethylcyclohexane-l,2-diamine (0.13 mL, 0.8 mmol) were added into the reaction mixture. The reaction mixture was allowed to stir at 90°C for 16 h. The reaction mixture was cooled to ambient temperature, filtered through celite and the filtrate was concentrated under reduced pressure. Product was purified by reverse phase Prep HPLC and lyophilized to afford 1-((S)-l-cyclopropylethyl)-3-(l-(4-(l,l,l-trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea (2-3, 160 mg). LCMS (ESI) Calcd. For C18H21F3N4O2: 382.2, found [M+H]+: 383.2.

[0281] Step-2: Synthesis of l-((S)-l-cyclopropylethyl)-3-(l-(4-(l,1, 1 -trifluor o-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea, & l-((S)-l-cyclopropylethyl)-3-(l-(4-(1, 1, l-trifhioro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea. The diastereomeric mixture of 1 -((S)- 1 -cyclopropylethyl)-3-(l -(4-(l, 1, 1 -trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea (2-3, 120 mg, 0.3 mmol) was submitted for HPLC SFC prep purification. The fractions obtained are lyophilized to yield peak 1 as 1-((S)-1-cyclopropylethyl)-3-(l-(4-((R)-l,l,l-trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea (50 mg) and peak 2 as l-((S)-l-cyclopropylethyl)-3-(l-(4-((S)-l,l,l-trifluoro-2- -197- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOhydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea (48 mg). Stereochemistry of both the compounds are arbitrarily assigned.

[0282] SFC method: SFC PREP PURIFICATION of sample has been completed on Waters SFC 80 instrument equipped with Waters 2489 UV / Visible Detector by using CHIRALPAK IG(30 mm x 250 mm ), 5p Column operating at 35 °C temperature, maintaining flow rate of 70 ml / min, using 60% CO2 in super critical state & 40% of [100% MeOH] as Mobile phase, Run this isocratic mixture up to 8.0 minutes and also maintained the isobaric condition of 100 bar at 282 nm wavelength.

[0283] 1 -((S)- 1 -cyclopropylethyl)-3 -(1 -(4-( 1,1,1 -trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea, (Peak 1): LCMS (ESI): Calcd. For C18H21F3N4O2: 382.2, found [M+H]+: 383.2. 'HNMR (400 MHz, DMSO-d6at 25°C) 611: 8.98 (s, 1H), 8.35-8.34 (m, 1H), 7.74-7.72 (m, 2H), 7.66-7.64 (m, 2H), 6.69-6.68 (m, 1H), 6.63 (s, 1H), 6.44-6.43 (m, 1H), 3.28-3.23 (m, 1H), 1.70 (s, 3H), 1.16-1.14 (m, 3H), 0.92-0.87 (m, 1H), 0.44-0.38 (m, 2H), 0.30-0.22 (m, 2H).

[0284] 1 -((S)- 1 -cyclopropylethyl)-3 -(1 -(4-( 1,1,1 -trifluoro-2-hydroxypropan-2-yl)phenyl)-lH-pyrazol-3-yl)urea, (Peak 2): LCMS (ESI): Calcd. For C18H21F3N4O2: 382.2, found [M+H]+: 383.2. 'HNMR (400 MHz, DMSO-d6at 25°C) 611: 8.99 (s, 1H), 8.35-8.34 (m, 1H), 7.74-7.72 (m, 2H), 7.66-7.64 (m, 2H), 6.71-6.69 (m, 1H), 6.64 (s, 1H), 6.44-6.43 (m, 1H), 3.28-3.23 (m, 1H), 1.70 (s, 3H), 1.16-1.14 (m, 3H), 0.91-0.88 (m, 1H), 0.45-0.38 (m, 2H), 0.30-0.20 (m, 2H).Example 15 - Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide

[0285] Step-1: Synthesis of (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide. To a stirred solution of 6-amino-N-methyl-pyridine-2-carboxamide (3-1, 0.6 mmol) in dichloromethane (8 mL) at -5 °C was added triethylamine (0.32 mL, 2.3 mmol) and triphosgene (60.8 mg, 0.4 mmol). The reaction mixture was stirred at -15 °C for 30 min and -198- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO(S)-8-chlorochroman-4-amine hydrochloride (3-2, 125 mg, 0.6 mmol) was added. The reaction mixture was stirred at ambient temperature for 2 h and volatiles were evaporated. The product was purified by reverse phase preparative HPLC to afford (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide (CIO). LCMS (ESI) Calcd. for C17H17CIN4O3: 360.1, found [M+H]+= 361.1. 'HNMR (400 MHz, DMSO-d6): 6H 9.03 (s, 1H), 8.15-8.13 (m, 1H), 7.91-7.82 (m, 3H), 7.53 (d, 1H), 7.35-7.27 (m, 2H), 6.91 (t, 1H), 5.01-4.98 (m, 1H), 4.43-4.39 (m, 1H), 4.31-4.26 (m, 1H), 2.75 (d, 3H), 2.19-2.16 (m, 1H), 2.07-2.03 (m, 1H).

[0286] Example 16 - MDDS Characterized by TK2 mutations or TYMP mutations

[0287] The purpose of these experiments was to evaluate the effect of small molecule activators targeted to POLG on mitochondrial DNA (mtDNA) recovery in primary fibroblasts derived from patients with thymidine kinase 2 (TK2) mutations or thymidine phosphorylase (TYMP) mutations, including TK2 R130W / 219inCG (inCG = insertion of CG), TYMP E289A / E289A, or TYMP E289A / c.516+2T> C.

[0288] Briefly, primary fibroblasts from patients with wild-type POLG and mutant TK2 or mutant TYMP were obtained. The cells were grown in Dulbecco's Modified Eagle Medium (DMEM) with 4.5 g / L D-glucose +10% Fetal Bovine Serum (FBS) until 100% confluency at 37°C in a 5% CO2 humidified cell incubator. mtDNA depletion was induced by adding 50 ng / mL EtBr to the culture medium for 7 days, after which the cells were washed with Earle's Balanced Salt Solution (EBSS) and the medium was changed to DMEM 4.5 g / L D-glucose + 0.1% FBS. On day 3 after the medium change, the cell cultures were treated with DMSO or the indicated compound at the indicated concentration for one or two weeks.

[0289] To measure mtDNA copy number, cell pellets were lysed in DNA lysis buffer A [0.1 M NaCl, 0.025 M EDTA, 0.01 M Tris pH 8.0, 0.5% SDS] supplemented with 0.1 mg / mL Proteinase K, and incubated for 1 h at 55 °C. Samples were then extracted using the Zymo DNA Extraction Kit. Samples were eluted in DNAse free water supplemented with RNAse A (1:100). Cell debris were pelleted by centrifugation and discarded, and supernatant were diluted before qPCR analysis. Relative mtDNA content was quantified by qPCR as the CytB / 18S ratio and analyzed using the 2-ΔΔCtmethod in Bio-Rad CFX Maestro. Absolute mtDNA content was quantified by qPCR of CytB and B2M using a plasmid standard curve-199- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOcontaining both targets, with copy numbers calculated in Bio-Rad CFX Maestro. Plotting and statistic analysis using Brown-Forsythe and Welch ANOVA test were done in GraphPad Prism. *p< 0.05, **p< 0.01, ***p< 0.001,0.0001.

[0290] The results are displayed in FIGs. 8A-8D. FIGs. 8A and 8B show that in quiescent TK2 R130W / 219inCG fibroblasts, mtDNA copy number recovered over time in DMSO controls. C3 (0.1 and 1 pM) showed no statistically significant difference versus DMSO at day 7 or day 14, while 1 pM C6 yielded significantly higher mtDNA copy number at day 7.

[0291] FIG. 8C shows that in quiescent TYMP E289A / E289A fibroblasts, mtDNA copy number recovered over time in DMSO controls. C3 (0.1 and 1 pM) showed no statistically significant difference versus DMSO at day 7 or day 14, while 0.1 pM C4 yielded significantly higher mtDNA copy number at day 14.

[0292] FIG. 8D shows that in quiescent TYMP E289A / c.516+2T> C fibroblasts, mtDNA copy number recovered overtime in DMSO controls. C3 (0.1 and 1 pM) showed no statistically significant difference versus DMSO at day 7 or day 14, while 0.1 pM C4 yielded significantly higher mtDNA copy number at day 14.

[0293] Primary fibroblasts were obtained from patients with mutations in TK2, MPV17, RRM2B, DGUOK, or TYMP identified in Table 6 below. Using similar methods as described in this Example, each patient derived fibroblast cell line with POLG mutations was treated with 1 pM pM of the indicated compound. Table 6 summarizes the ability of the tested compounds in improving mtDNA recovery compared to control (DM SO). Compounds where the increase in mtDNA was statistically significant compared to control (DMSO), with p<0.05, are noted with an “A.” Compounds where the increase in mtDNA was statistically significant compared to control (DMSO), with p >0.05 but < 0.1, are noted with an “B.” Compounds where the increase in mtDNA when compared to control (DMSO) had a p>0.1 are noted with an “C”, and compounds where the increase is not significant due to natural mtDNA recovery in the DMSO control are noted with a “D.”f zFv-y" A N JI N AA N A OHVH His compound 9 (C9). (S)-6-(3-(8-chlorochroman-4-yl)ureido)-N-methylpicolinamide is Compound 10 (CIO).-200- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOTable 6. Ability of tested compounds to improve mtDNA recoveryCompoundMDDS Patientfibroblasts C5 Cl C3 C4 C9 C2 CIO TK2 R123P / R123P B D D A cTK2 R130W / 219insCG A D B CMPV17 A C A A C c A RRM2B (E85* / +) B A A ANHDF (wt fibroblasts) A A cDGUOKR39G / F256*(#123) C C cDGUOKR39G / F256*(#125) A CTYMP E289A / E289A C ATYMP E289A / C1160- 1G> C C CTYMPE289A / c516+2T> Cc A

[0294] Example 17 - Wild-type Neuron Stem Cells

[0295] The purpose of these experiments was to evaluate the effect of small molecule POLG activators described herein on mitochondrial DNA (mtDNA) recovery in neuron stem cells (NSC) differentiated from PGP2 WT iPSC.

[0296] Briefly, PGP2 hiPS cells were cultured and expanded in mTeSR Plus complete medium on iMatrix511 coated plates and passaged using StemPro Accutase. hiPS cells were differentiated into neural stem cells (NSCs) under feeder-free conditions in 3% CO2. WT NSCs were cultured on Matrigel coated plates in StemDiff Neural Progenitor Medium supplemented with 5 pM rho kinase inhibitor. The cells were maintained in a 37 °C humidified incubator with 5% CO2. NSCs were treated with DMSO or C6 at the indicated concentrations for a total of seven days. After treatment, cells were detachedwith Accutase and either collected for further molecular analysis or replated for mitochondrial respiration test.-201- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0297] To measure mtDNA copy number, cell pellets were lysed in DNA lysis buffer A [0.1 M NaCl, 0.025 M EDTA, 0.01 M Tris pH 8.0, 0.5% SDS] supplemented with 0.1 mg / mL Proteinase K, and incubated for 1 h at 55 °C. Samples were then extracted using the Zymo DNA Extraction Kit. Samples were eluted in DNAse free water supplemented with RNAse A (1:100). Cell debris were pelleted by centrifugation and discarded, and supernatant were diluted before qPCR analysis. Relative mtDNA content was quantified by qPCR as the CytB / 18S ratio and analyzed using the 2-ΔΔCtmethod in Bio-Rad CFX Maestro. Absolute mtDNA content was quantified by qPCR of CytB and B2M using a plasmid standard curve containing both targets, with copy numbers calculated in Bio-Rad CFX Maestro. Plotting and statistic analysis using Brown-Forsythe and Welch ANOVA test were done in GraphPad Prism. *p< 0.05, **p< 0.01, ***p< 0.001,0.0001.

[0298] The results are shown in FIG. 9, where FIG. 9 demonstrates that C6 did not change the mtDNA level in WT NSCs over the course of treatment.

[0299] Example 18 - Survival of TK2 Knockout and DGUOK KO Mouse Models

[0300] The purpose of these experiments was to evaluate the effects compounds disclosed herein in TK2 Knockout (KO) mice or DGUOK KO mice.

[0301] A TK2 KO mouse model was established and the TK2 KO mice to be treated were genotyped to confirm the knockout of TK2. C3 or C4 was administered daily form day 4 to day 14, and tissues were collected on day 15 to determine the effect on survival of the mice compared to vehicle-treated TK2 KO mice. Body weight, surface body temperature, and general behavior was recorded daily.

[0302] DNA was extracted from frozen tissue using Qiagen Kits following the manufactures instructions. DNA concentration and DNA quality was then determined and all DNA samples were diluted in IDTE buffer. 2.5 pL of DNA (4 ng / pL) or gBlock standard were added per well with 7.5 pL of Master Mix ((including mouse mt-Cytb and mouse Angl). Cycle Threshold (Ct) values for each well were calculated by running a standard PCR protocol.-202- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO

[0303] The results of the study, dose, percent increase in survival over control (vehicle-treated TK2 KO mice), and percent increase in liver mtDNA are summarized in Table 7 below.Table 7. Results of TK2 KO Mice treated with C3 or C4Compound Survival Liver MtDNA (Dose, mg / kg) (% increase over control) (% increase over control) C3 (3) 6% C3 (10) 23% 14% C3 (100) 47% 60% C3 (300) 47% C4(10) 16% C4(10) 31% C4(100) 25% C4 (200) 33%

[0304] TK2 KO mice treated with C3 or C4 had a statistically significant increase in survival compared to vehicle-treated TK2 KO mice. An increase in liver mtDNA was also observed in mice treated with C3 compared to control.

[0305] A similar experiment was conducted with DGUOK KO mice. C57BL / 6NJ-DGUOK+ / -, heterozygous (HET) mice were bred together to generate DGUOK KO, and genotyping was conducted to confirm the knockout of DGUOK. Cl, C3, C4, or C7 was administered daily for 1-2 months to determine the effect on liver health of the mice compared to vehicle-treated DGUOK KO mice. Body weight, surface body temperature, and general behavior was recorded daily.

[0306] Plasma samples and clinical chemistry: On the day of sacrifice, two hours after the last dose, blood sampling for plasma collection was performed by cardiac bleed on animals. Blood was collected in lithium heparin coated capillaries. Plasma was isolated from blood by centrifugation for 10 minutes at 2,000 g in a refrigerated centrifuge. Following centrifugation, plasma samples were snap-frozen. Blood biochemistry analysis was performed to measure-203- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOAlanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline phosphatase (ALP), and Total Bilirubin.

[0307] Total DNA extraction and mtDNA assay: The liver was collected, dissected on ice, quickly rinsed with ice cold saline, and snap-frozen in liquid nitrogen. Tissue samples were collected tubes prefilled with beads (Precellys, CK282 mL tubes). Tubes were weighed and then quickly snap-frozen in liquid nitrogen. Total DNA extraction was performed using DNeasy Blood & Tissue kits. mtDNA levels were measured qPCR using standard curves and reported as absolute mt-NDl, mt-CytB mitochondrial genes and Angl (nDNA) copy numbers.

[0308] Liver transaminases were analyzed by a clinical analyzer. Blood biochemistry analysis was performed in an accredited veterinary laboratory (BIO VET). Liver transaminases were first subject to a ROUT outlier analysis then analyzed with a one-way ANOVA followed by a Fisher’s LSD comparing values to the KO vehicle-treated mice.

[0309] The results of multiple studies, dose, percent decrease in transaminase activity compared to control (vehicle-treated DGUOK KO mice), and percent increase in liver mtDNA are summarized in Table 8 below. Transaminase activity represents either ALT or ALP activity.Table 8. Results of DGUOK KO Mice treated with C3 or C4Compound Transaminase Activity Liver MtDNA (Dose, mg / kg) (% decrease from control) (% increase over control) C3 (10) C3 (100) 53% 28%** C3 (300) 34%** 11% C7 (...

Claims

Attorney Docket No. PTZ-012WOWHAT IS CLAIMED IS1. A method of treating a Mitochondrial DNA (mtDNA) Depletion Syndrome (MDDS) in a subject in need thereof comprising:a. optionally identifying a subject diagnosed with, or at risk of developing, a MDDS; andb. administering a therapeutically effective amount of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, wherein the subject does not have a mutation or deletion in the DNA polymerase y gene (POLG).

2. A method of treating a Primary Mitochondrial Disorder (PMD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, wherein the subject does not have a mutation or deletion in the DNA polymerase y gene (POLG).

3. The method of claim 1 or 2, wherein the subject has one or more of: mtDNA deletions, mtDNA mutations, impaired mitochondrial oxidative phosphorylation, impaired recycling of mtDNA nucleotides, a reduction in the amount of mtDNA, impaired mtDNA function, impaired replication of mtDNA, impaired mechanisms of mtDNA, unbalanced nucleotide pools, low processivity, a defect in DNA-binding function, decreased DNA-binding affinity, reduced catalytic efficiency, a reduction in thymidine kinase activity, a reduction in Twinkle helicase activity, a reduction in thymidine phosphorylase activity, a reduction in deoxyguanosine kinase activity, a reduction in Ribonucleotide reductase M2B activity, a reduction in ribonuclease Hl (RNASEH1) activity, a reduction in mitochondrial SSBP1 activity, a reduction in Mitochondrial Genome Maintenance Exonuclease 1 (MGME1) activity, a reduction in DNA2 nuclease / helicase activity, a reduction in adenine nucleotide translocase type 1 (ANTI) protein activity, a reduction in succinyl-CoA ligase (SUCL) activity, a reduction in MP VI 7 protein activity, a reduction in activity of ATP synthase enzyme, or any combination thereof.-207- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO4. The method of any one of claims 1-3, wherein the subject has a mutation in a gene selected from the group consisting of thymidine kinase 2 (TK2), twinkle (TWNK or C10ORF2), Thymidine Phosphorylase (TYMP), Deoxy guanosine Kinase (DGUOK), Ribonucleotide Reductase Regulatory Subunit M2B (RRM2B), Ribonuclease Hl (RNASEH1), Single-Stranded DNA Binding Protein 1 (SSBP1), Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA Replication Helicase / Nuclease 2 (DNA2), Adenine Nucleotide Translocator 1 (ANTI; SLC25A4), Succinate-CoA Ligase GDP -Forming Subunit Alpha (SUCLG1), Succinate-CoA Ligase ADP- Forming Subunit Beta (SUCLA2), MPV17 Mitochondrial Inner Membrane Protein (MPV17), Mitochondrially Encoded ATP Synthase Membrane Subunit 6 (MT- ATP6), Mitochondrially Encoded tRNA Leucine 1 (MT-TL1), Mitochondrially Encoded tRNA Histidine (MT-TH), Mitochondrially Encoded tRNA Serine 1 (MT- TS1, OPA1 (OPA1 mitochondrial dynamin like GTPase), FBXL4 (F-box and leucine rich repeat protein 4), and AGK (acylglycerol kinase).

5. The method of any one of claims 1-3, wherein the subject has a mutation in a gene selected from the group consisting of thymidine kinase 2 (TK2), twinkle (TWNK or C10ORF2), Thymidine Phosphorylase (TYMP), Deoxy guanosine Kinase (DGUOK), Ribonucleotide Reductase Regulatory Subunit M2B (RRM2B), Ribonuclease Hl (RNASEH1), Single-Stranded DNA Binding Protein 1 (SSBP1), Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA Replication Helicase / Nuclease 2 (DNA2), Adenine Nucleotide Translocator 1 (ANTI; SLC25A4), Succinate-CoA Ligase GDP -Forming Subunit Alpha (SUCLG1), Succinate-CoA Ligase ADP- Forming Subunit Beta (SUCLA2), MPV17 Mitochondrial Inner Membrane Protein (MPV17), Mitochondrially Encoded ATP Synthase Membrane Subunit 6 (MT- ATP6), Mitochondrially Encoded tRNA Leucine 1 (MT-TL1), Mitochondrially Encoded tRNA Histidine (MT-TH), and Mitochondrially Encoded tRNA Serine 1 (MT-TS1).

6. The method of any one of claims 1-5, wherein the subject has a mutation in a gene selected from the group consisting of TK2, twinkle (TWNK or C10ORF2), TYMP, DGUOK, MPV17, and RRM2B.-208- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO7. The method of any one of claims 1-5, wherein the subject has a mutation in a gene selected from the group consisting of TK2, DGUOK, SUCLA2, SUCLG1, MPV17, RRM2B, and MGME1.

8. The method of claim 5 or 6, wherein:(a) the subject has a mutation in the TK2 gene; and(b) the MDDS is thymidine kinase 2 deficiency (TK2D).

9. The method of any one of claims 1-6, wherein the subject has unbalanced nucleotide pools.

10. The method of claim 5 or 6, wherein:(a) the subject has a mutation in the TWNKLE gene; and(b) the PMD or MDDS is infantile onset spinocerebellar ataxia (IOSCA), ataxia neuropathy spectrum, infantile-onset spinocerebellar ataxia, or progressive external ophthalmoplegia.

11. The method of claim 5 or 6, wherein:(a) the subject has a mutation in the TYMP gene; and(b) the PMD or MDDS is mitochondrial neurogastrointestinal encephalomyopathy (MNGIE).

12. The method of claim 5 or 6, wherein:(a) the subject has a mutation in the DGUOK gene; and(b) the PMD or MDDS is Deoxyguanosine kinase (DGUOK) deficiency.

13. The method of claim 5 or 6, wherein:(a) the subject has a mutation in the RRM2B gene; and(b) the PMD or MDDS is encephalomyopathic form with renal tubulopathy (RRM2B-MDDS).

14. The method of claim 5, wherein:(a) the subject has a mutation in the RNASEH1 gene; and-209- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO(b) the PMD or MDDS is a mitochondrial DNA maintenance disorder, adult-onset mitochondrial encephalomyopathy, or type 1 diabetes.

15. The method of claim 5, wherein:(a) the subject has a mutation in the SSBP1 gene; and(b) the PMD or MDDS is Optic Atrophy 13 With Retinal And Foveal Abnormalities or Cone-Rod Dystrophy 2.

16. The method of claim 5, wherein:(a) the subject has a mutation in the MGME1 gene; and(b) the PMD or MDDS is mitochondrial DNA depletion syndrome type 11 (MTDPS11).

17. The method of claim 5, wherein:(a) the subject has a mutation in the DNA2 gene; and(b) the PMD or MDDS is progressive muscular dystrophy, progressive myopathy, or mitochondrial DNA depletion syndrome due to impaired replication and repair mechanisms of the mitochondrial DNA.

18. The method of claim 5, wherein:(a) the subject has a mutation in the ANTI (SLC25A4) gene; and (b) the PMD or MDDS is Progressive external ophthalmoplegia (PEO), Cardiomyopathy and skeletal myopathy, Mitochondrial DNA depletion syndrome 12A (MTDPS-12A), Bipolar disorder, exercise intolerance, hyperlactatemia, cataracts, arterial hypertension, depression, or scoliosis.

19. The method of claim 5, wherein:(a) the subject has a mutation in the SUCLG1 gene; and(b) the PMD or MDDS is SUCLG1 -related mitochondrial DNA (mtDNA) depletion syndrome.

20. The method of claim 5, wherein:(a) the subject has a mutation in the SUCLA2 gene; and-210- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO(b) the PMD or MDDS is Mitochondrial DNA depletion syndrome or Pyruvate dehydrogenase El-alpha deficiency.

21. The method of claim 5, wherein:(a) the subject has a mutation in the MP VI 7 gene; and(b) the PMD or MDDS is MPV17-related hepatocerebral mitochondrial DNA depletion syndrome.

22. The method of claim 5, wherein:(a) the subject has a mutation in the MT-TL1 gene; and(b) the PMD or MDDS is Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Episodes (MELAS).

23. The method of claim 5, wherein:(a) the subject has a mutation in the MT-TL1 gene, the MT-TH, the MT- TS1 gene, or any combination thereof; and(b) the PMD or MDDS is Myoclonic Epilepsy and Ragged Red Fibers (MERRF).

24. The method of claim 5, wherein:(a) the subject has a mutation in the MT-ATP6 gene; and(b) the PMD or MDDS is neuropathy, ataxia, and retinitis pigmentosa (NARP) syndrome.

25. The method of claim 1 or 2, wherein administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof:(a) results in upregulating levels of mitochondrial DNA (mtDNA) in the subject; (b) results in dose-dependent increases in mtDNA production in the subject; (c) improves mtDNA recovery following depletion in the subject;(d) results in an increase in mtDNA production in the subject;(e) results in an increase in mtDNA copy number per cell in the subject;(f) results in restoration of mtDNA levels in the subject, and related improvement in cellular function;-211- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO(g) results in an increase in mtDNA production in subject-derived fibroblasts; (h) increases cellular respiration in the subject;(i) results in an increase in cellular energy in the subject;(j) results in improved mitochondrial oxidative phosphorylation in the subject; (k) results in improved recycling of mtDNA nucleotides in the subject;(l) results in improved mtDNA function in the subject;(m) results in improved replication of mtDNA in the subject;(n) results in improved mechanisms of mtDNA in the subject;(o) shifts ATP production rate to favor oxidative phosphorylation in the subject; (p) results in improved liver health for the subject;(r) results in improved catalytic efficiency in the subject;(s) results in an increase in thymidine kinase activity;(t) results in an increase in Twinkle helicase activity;(u) results in an increase in thymidine phosphorylase activity;(v) results in an increase in deoxyguanosine kinase activity;(w) results in an increase in Ribonucleotide reductase M2B activity;(x) results in an increase in ribonuclease Hl (RNASEH1) activity;(y) results in an increase in mitochondrial SSBP1 activity;(z) results in an increase in Mitochondrial Genome Maintenance Exonuclease 1 (MGME1) activity;(aa) results in an increase in DNA2 nuclease / helicase activity;(bb) results in an increase in adenine nucleotide translocase type 1 (ANTI) protein activity;(cc) results in an increase in succinyl-CoA ligase (SUCL) activity;(dd) results in an increase in MP VI 7 protein activity;(ee) results in an increase in activity of ATP synthase enzyme: or(ff) any combination thereof.

26. The method of claim 25, wherein upregulation of healthy mtDNA in the subject occurs in multiple organs, including the brain.-212- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO27. The method of claim 25 or 26, wherein the mtDNA level in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, as compared to the mtDNA level present in the subject prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

28. The method of claim 27, wherein an increase in the mtDNA level in the subject is measured using a clinically acceptable technique.

29. The method of claim 28, wherein the clinically acceptable technique is PCR, Quantitative PCR (qPCR), digital PCR (dPCR), genomic methods such as whole exome sequences (WES) and whole genome sequencing (WGS), Low pass whole genome sequencing (IpWGS), or any combination thereof.

30. The method of claim 25, wherein:(a) the processivity and / or activity of an enzyme or protein in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, or at least about 100%, as compared to activity of the enzyme prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof; and (b) the enzyme or protein is selected from the group consisting of Twinkle helicase, thymidine phosphorylase, deoxyguanosine kinase, Ribonucleotide reductase M2B, ribonuclease Hl (RNASEH1), mitochondrial SSBP1, Mitochondrial Genome Maintenance Exonuclease 1 (MGME1), DNA2 nuclease / helicase, adenine nucleotide translocase type 1 (ANTI) protein, succinyl-CoA ligase (SUCL), MP VI 7 protein, and ATP synthase enzyme.-213- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO31. The method of claim 30, wherein the improvement in the processivity or activity of the protein or enzyme in the subject is measured using a clinically acceptable technique.

32. The method of claim 25, wherein the mtDNA copy number per cell in the subject increases by at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 99%, at least about 100%, at least about 125%, at least about 150%, at least about 175%, or at least about 200% as compared to the mtDNA copy number per cell present in the subject prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

33. The method of claim 25, wherein the improved liver health for the subject is determined by:(a) comparing the amount of liver enzymes and / or liver mtDNA in the subject prior to treatment and following treatment with the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof;(b) identifying a decreased presence of liver disease markers in the subject prior to treatment and following treatment with the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof; or(c) any combination thereof.

34. The method of any one of claims 1-33, wherein the therapeutically effective amount of the compound is a dose ranging from about 5 mg up to about 2000 mg.

35. The method of any one of claims 1-34, wherein the therapeutically effective amount of the compound is a dose ranging from about 30 to about 1000 mg.

36. The method of any one of claims 1-33, wherein the therapeutically effective amount of the compound is a dose ranging from 5 mg / kg up to about 1000 mg / kg.-214- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WO37. The method of any one of claims 1-36, wherein the compound is administered once per day.

38. The method of any one of claims 1-33, wherein the therapeutically effective amount of the compound is below the nonclinical no-observed-adverse-effect level (NOAEL).

39. The method of any one of claims 1-7, wherein the PMD or MDDS is inherited.

40. The method of any one of claims 1-7, wherein the therapeutically effective amount of a compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof an improves one or more symptoms of the PMD or MDDS disorder.

41. The method of claim 40, wherein the improvement in the one or more symptoms are measured using a clinically acceptable method.

42. The method of claim 41, wherein the symptom is selected from the group consisting of muscle function, muscle weakness, muscle atrophy, hypotonia, dystonia, loss of muscle coordination, loss of motor skills, sensory ataxia, epilepsy, encephalopathy with seizures, involuntary movements, seizures, status epilepticus, epilepsia partialis continua, focal motor seizures, generalized status epilepticus, refractory convulsive status epilepticus, progressive weakness of the extraocular muscles, bilateral symmetrical ptosis, ptosis, ataxia, parkinsonism, liver function, liver disease, hepatopathy, hepatic impairment, hypoglycaemia, hepatic steatosis, developmental delay, growth retardation, gastrointestinal issues, weight loss, nausea, vomiting, diarrhea or persistent diarrhea, cachexia related to gastrointestinal dysmotility, dysphagia, cerebellar ataxia, brain abnormalities, neurodevelopmental regression, myopathies, eye problems, ophthalmoplegia, cataracts, strabismus, optic atrophy, external ophthalmoplegia, hearing loss, sensorineural hearing impairment or deafness, cardiac problems, cardiomyopathies, heart disease, visual problems, retinopathy, renal dysfunction, renal disease, diabetes mellitus, proximal myopathy, encephalomyopathy, neuropathy, peripheral neuropathy, sensory neuropathy, distal myopathy, demyelinating neuropathy, neuropathic pain, exercise intolerance, lactic acidosis, myoclonus, microcephaly, sleep disturbance, rhabdomyolysis, contractures,-215- IPTS / 200255054.4 157476-454671Attorney Docket No. PTZ-012WOhypothermia, hypoglycemia, myoclonus, myopathy, depression, dysarthria, premature menopause, ragged-red muscle fibres, lipodystrophy, and any combination thereof.

43. The method of claim 41 or 42, wherein the symptom is ataxia or seizures.

44. The method of any one of claims 1-7, wherein the subject is:(a) a pediatric patient;(b) an adolescent or young adult; or(c) an adult.

45. The method of claim 43, wherein the pediatric patient is less than 12 years old.

46. The method of any one of claims 1-7, wherein the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof, is a POLg activator compound.

47. The method of any one of claims 1-46, wherein the compound is present in a pharmaceutical composition comprising at least one pharmaceutically acceptable excipient.

48. The method of claim 47, wherein the compound or composition is administered orally, intrathecally, enterally, or intravenously.

49. The method of any one of claims 1-48, wherein the compound is l-((S)-8- chlorochroman-4-yl)-3- (2-(l -hydroxy ethyl)thiazol-4-yl)urea, or a pharmaceutically acceptable salt thereof.-216- IPTS / 200255054.4 157476-454671

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