Methods of treatment for POLG mutation disorders

Abstract

Provided are methods of treating a Primary Mitochondrial Disorder (PMD) or Mitochondrial DNA Depletion Syndrome (MDDS) in a subject in need thereof comprising: administering a therapeutically effective amount of a compound listed in Table 1, Table 2, Table 3, Table 4, or Table 5. The subject may have one or more mutations or deletions in the DNA polymerase γ gene (POLG).

Description

Attorney Docket No. PTZ-011WOMETHODS OF TREATMENT FOR POLG MUTATION DISORDERS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U. S. Provisional Application No. 63 / 737,034, filed December 20, 2024, the content of which is herein incorporated by reference in its entirety.BACKGROUND

[0002] Mitochondrial disease refers to a heterogeneous group of disorders resulting in defective cellular energy production due to abnormal oxidative phosphorylation (OXPHOS). Mitochondrial disease is categorized into Primary Mitochondrial Disease (PMD) and Secondary Mitochondrial Disease (SMD).

[0003] PMD may arise from pathogenic mutations in genes encoded by either the mtDNA or nuclear DNA (nDNA), which compromise normal mitochondrial respiratory function. One gene which may cause PMD when mutated is the DNA polymerase y (POLy) gene.

[0004] The POLy gene (e.g., POLG gene) encodes a mitochondrial DNA polymerase responsible for the replication of the mitochondrial genome. POLy (e.g., POLG gene) is composed of a 140 kDa catalytic subunit that is encoded by POLG at chromosomal locus 15q25, and a 55 kDa accessory subunit that forms a dimer and is encoded by POLG2 at chromosomal locus 17q24.14-6, collectively the “POLG gene”. POLy has DNA polymerase, 3’ to 5’ exonuclease and 5 ’-deoxyribose phosphate (5’-dRP) lyase activities. This subunit contains an amino-terminal exonuclease domain connected by a linker region to the carboxyterminal polymerase domain. POLy2 enhances polymerase processivity by increasing the affinity of the catalytic subunit for DNA.

[0005] As the only known DNA polymerase in mitochondria, POLy is required for all replication and repair functions for mtDNA.

[0006] Mutations in POLG represent the most prevalent single-gene cause of mtDNA depletion disorders, such as depletion disorders known as mitochondrial DNA depletion syndromes, a subset of PMD. More than 300 pathogenic mutations of POLy have been reported, as presented in the Human DNA Polymerase Gamma Mutation Database.Attorney Docket No. PTZ-011WO

[0007] A subset of PMD, called Mitochondrial DNA depletion syndromes (MDDS), is generally characterized due to defects in mtDNA maintenance that may be caused by mutations in nuclear genes that function in mtDNA replication, such as POLG.

[0008] There is an ongoing need for therapeutics that treat mutated POLy-related disorders, such as PMD and MDDS.SUMMARY OF THE INVENTION

[0009] According to one aspect of the present disclosure, encompassed is a method of treating 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. In some embodiments, the subject is identified to have one or more mutations or deletions in the DNA polymerase y (POLG) gene.

[0010] According to another aspect of the present disclosure, encompassed is a method of treating Mitochondrial DNA Depletion Syndrome (MDDS) in a subject in need thereof, the method comprising optionally identifying a subject diagnosed with, or at a risk of developing, an 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, wherein the subject has one or more mutations or deletions in the DNA polymerase y gene (POLG).

[0011] In one embodiment, the subject at risk of developing PMD or MDDS has one of more symptoms of having a mutation in the POLG gene (e.g., POLy gene). In one embodiment, the symptom is neurological, ophthalmological, gastrointestinal, endocrinological, myopathy, or hepatopathy. In one embodiment, (i) the neurological symptom is seizure (focal, myoclonic, epilepsia partialis continua, convulsive status epilepticus), ataxia, peripheral neuropathy, or sensorineural hearing loss, (ii) the ophthalmological symptom is ptosis, nystagmus, progressive external ophthalmoplegia, cataract, cortical blindness, or pigmentary retinopathy, (iii) the gastrointestinal symptom is a feeding difficulty, chronic diarrhea, or vomiting, (iv) the endocrinological symptom is diabetes mellitus type 1, diabetes mellitus type 2, or adrenal insufficiency, (v) the myopathy symptom is muscle weakness, myalgia, muscle fatigue, muscle stiffness, or (v) theAttorney Docket No. PTZ-011WOhepatopathy symptom is liver failure (acute, chronic, or recurrent), cholestasis, liver fibrosis, or elevated transaminases. In one embodiment, the neurological symptom is a seizure (focal, myoclonic, epilepsia partialis continua, convulsive status epilepticus). In one embodiment, the neurological symptom is ataxia. In one embodiment, the hepatopathy symptom is liver failure (acute, chronic, or recurrent).

[0012] In one embodiment, diagnosing a subject comprises sequencing the subject’s POLG gene. In one embodiment, the sequence of the subject’s POLG gene reveals one or more mutations in the POLG gene selected from the group consisting of: R3P, S28C, G11D, Q43R, Q45R, Q49E, Q68X, A(CAG)n, S64L, L79F, L83P, H110Y, P116Q, D122Y, D136E, A143V, P163S, R193Q, C224Y, R227P, R227W, R232G, R232H, W235X, P241L, L244P, T251I, G268A, R275X, R275Q, H277L, Y282D, G303R, L304R, S305R, Q308H, R309L, R309H, W312R, K319E, P324S, T326fs61X, T326fs387X, W347_L356del, W347fs356X, E358A, R374X, G380D, E386H, R386C, L392V, L392W, R417T, R417X, C418R, L424Gfs28X, L424X, G426S, L428P, G426S, M430L, G431V, S433C, M340L, G431V, S433C, Q449X, T452X, Y452X, L463F, M464T, A467T, N468D, Q497H, K498T, S511N, K512M, G517V, R546C, K561M, R562Q, H569Q, R574W, R579W, W585X, P587L, G588D, P589L, L591F, R597W, K601E, M603L, L605R, R617C, G621D, L623W, P625R, R627W, R627Q, R628Q, P648R, E662K, R709X, Q715X, R722H, N736S, G737R, G746S, W748S, F749S, L752P, H754Q, K755E, G763R, P765T, A767D, K768E, G785fs21X, R790H, M797del, A804T, R807P, R807C, R807H, Y831C, G848S, T849X, T849H, T851A, R852C, R852H, R853Q, R853W, V855A, V855L, A862T, N864S, R869Q, E873X, Q879H, T885S, L886P, G888S, G888D, A889T, D890A, E895G, F907I, T914P, T914A, W918R, M919T, G923D, K925fsX, K925Rfs42X, D930N, H932Y, S933R, R943H, R943C, H945L, K947R, Y951N, R953C, Y955C, A957S, A957P, A957V, F961S, A962T, R964C, L965X, L966R, G975X, Y995C, S998L, W1020X, Q1024X, V1044A, R1047Q, R1047W, K1050X, G1051R, G1052S, G1052D, E1054fs, P1073L, G1076V, C1077G, I1079L, S1080T, SI 0801, R1081P, R1091Q, S1095G, S1095R, R1096C, R1096H, S1104C, S1104F, A1105T, VI 1061, Hl HOY, L1113P, R1128H, H1134R, E1136K, R1138C, R1142W, E1143G, E1145G, D1145GfsX9, R1146C, Q1154R, M1163R, F1164I, L1173fsX, S1176L, D1184N, D1184L, I1185T, R1187W, C1188R, K1191N, K1191R, D1196N, T1199X, G1205A, Y1210fs6X,Attorney Docket No. PTZ-011WOQ1214X, Y1210fsl216X, S1230F, Q1236H, X1240Q / Y + 35aa, and any combination thereof.

[0013] In one embodiment, the one or more mutations is R232H, R309C, A467T, W748S, G848S, Y955C, El 143G, T251I-P987L, A467T and G484S, W748S + El 143G and R232H, G303R and A467T, G737R and R232H, F197S and T914P, A467T and R574W, Y955C, T251I and P587L, W748S and El 143G, or any combination thereof. In one embodiment, the one or more mutations is A467T, W748S, G848S, R232H, and any combination thereof. In one embodiment, the one or more POLG mutations is R232H. In one embodiment, the one or more POLG mutations is R309C. In one embodiment, the one or more POLG mutations is A467T. In one embodiment, the one or more POLG mutations is W748S. In one embodiment, the one or more POLG mutations is G848S. In one embodiment, the one or more POLG mutations is Y955C. In one embodiment, the one or more POLG mutations is E1143G. In one embodiment, the one or more POLG mutations is T251I-P987L. In one embodiment, the one or more POLG mutations is A467T and G484S. In one embodiment, the one or more POLG mutations is W748S and E1143G. In one embodiment, the one or more POLG mutations is W748S, E1143G and R232H. In one embodiment, the one or more POLG mutations is G303R and A467T. In one embodiment, the one or more POLG mutations is G737R and R232H. In one embodiment, the one or more POLG mutations is F197S and T914P. In one embodiment, the one or more POLG mutations is A467T and R574W. In one embodiment, the one or more POLG mutations is T251I and P587L.

[0014] In one embodiment, the POLG mutation results in one or more of: mitochondrial DNA (mtDNA) deletions, reduced mtDNA levels, a reduction in mtDNA POLy polymerase activity, low processivity of the POLy polymerase, a defect in the mtDNA-binding function of the POLy polymerase, a decrease in the mtDNA-binding affinity of the POLy polymerase, or any combination thereof.

[0015] In one embodiment, the POLG mutation results in lower levels of mtDNA copy number in a tissue specific cell type of the subject compared to the cell type in a subject who does not have a POLG mutation.

[0016] In one embodiment, the tissue specific cell type is selected from the group consisting of a fibroblast, hepatocyte, neuronal, and muscle.Attorney Docket No. PTZ-011WO

[0017] In one embodiment, administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5: (a) results in upregulating levels of healthy 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 mitochondrial DNA (mtDNA) production in the subject; (e) results in an increase in mitochondrial DNA (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) improves the processivity of a POLy protein in the subject; (i) increases cellular respiration in the subject; (j) shifts ATP production rate to favor oxidative phosphorylation in the subject; (k) results in improved liver health for the subject; or (1) any combination thereof.

[0018] In one embodiment, the increase in the mtDNA copy number per cell is 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’s cell prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5.

[0019] In one embodiment, the improvement of the processivity of the POLy protein is 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 protein prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5.

[0020] In one embodiment, the MDDS disorder characterized by a mutation in POLG is selected from the group consisting of Alpers-Huttenlocher syndrome (AHS), myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), mitochondrial recessive ataxia syndrome (MIRAS), progressive external ophthalmoplegia (PEO), mitochondrial encephalomyopathyAttorney Docket No. PTZ-011WO(MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE), sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO), and spinocerebellar ataxia with epilepsy (SCAE).

[0021] In one embodiment: (a) the MDDS disorder characterized by a mutation in POLG is ataxia neuropathy spectrum (ANS)and the POLG mutation is W748S; (b) the MDDS is Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia, Ataxia neuropathy spectrum or sensory ataxia neuropathy dysarthria and ophthalmoplegia and the POLG mutation is A467T; (c) the MDDS is AHS and the POLG mutation is Gly848, G848S, T851A, R852C, R853Q, or any combination thereof; (d) the MDDS is AHS and the OLG mutation is G11D, Q68X, L79F, L83P, A143V, C224Y, R227P, R227W, R232G, R232H, W235X, L244P, T251I, H277L, Y282D, G303R, L304R, S305R, R309H, T326fs387X, W347fs356X, E358A, R374X, E386H, R417T, R417X, C418R, L424X, G426S, L428P, A467T, G517V, K561M, H569Q, R574W, P587L, P589L, L605R, P625R, R627Q, Q715X, R722H, G737R, W748S, F749S, L752P, H754Q, A767D, R790H, M797del, R807H, G848S, T849X, T851A, R852C, R852H, R853Q, V855L, E873X, Q879H, T885S, L886P, G888S, G888D, E895G, T914P, T914A, K925fsX, D930N, R943C, A957P, A957V, L966R, G975X, W1020X, Q1024X, V1044A, R1047W, K1050X, P1073L, C1077G, S1080I, R1091Q, S1095R, R1096C, R1096H, H1110Y, L1113P, H1134R, E1136K, E1143G, D1145GfsX9, M1163R, L1173fsX, I1185T, R1187W, C1188R, K1191N, K1191R, Y1210fsl216X,, and any combination thereof; (e) the MDDS is PEO and the POLG mutation is T251I and P587L amino acid substitutions and / or Y955C; (f) the MDDS is autosomal dominant PEO and the POLG mutation is S511N, G293D, S933R, R943C, R943H, H945L, K947R, R953C, Y955C, A957S, F961S, I1079L, S1095R, A1105T, and any combination thereof; (g) the MDDS is autosomal recessive PEO and the POLG mutation is R3P, S28C, T2511, R275X, R275Q, L304R, Q308H, R309L, K319E, R386C, M430L, L463F, A467T, N468D, G517V, R574W, P587L, R597W, M603L, R627W, P648R, R722H, G737R, G746S, G763R, c.2354Gins, G848S, R853W, A862T, N864S, R869Q, W918R, M919T, H932Y, S998L, R1047W, G1051R, R1081P, V1106I, R1138C, F1164I, S1176L, D1184L, D1184N, K1191N, T1199X, Q1214X, X1240Q / Y + 35aa, and any combination thereof; (h) the MDDS is sporadic PEO and the POLG mutation is P163S, R227W, G268A, W312R, G380D, L424X, G431V, S433C, Y452X, R562Q, R579W, W585X, R709X, R807P, A889T, R1047Q, G1076V, R1096C,Attorney Docket No. PTZ-011WOS1104F, S1104C, and any combination thereof; or (i) the MDDS is ataxia neuropathy syndrome (ANS), MIRAS, SANDO, or SCAE and the POLG mutation is G11D, D122Y, L304R, G426S, M464T, A467T, Q497H, L591F, K601E, R627Q, R627W, P648R, N736S, W748S, G763R, P765T, K768E, R807C, A862T, R869Q, Y951N, A962T, R964C, L965X, S1080T, E1143G, and any combination thereof.

[0022] In one embodiment, the MDDS disorder characterized by a mutation in POLG is Alpers-Huttenlocher syndrome (AHS) and the symptom is selected from the group consisting of focal motor seizures, generalized status epilepticus, refractory convulsive status epilepticus, developmental delay, neurodevelopmental regression, renal dysfunction, hypotonia, epilepsia partialis continua, and any combination thereof.

[0023] In one embodiment, the MDDS disorder characterized by a mutation in POLG 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.

[0024] In one embodiment, the MDDS disorder characterized by a mutation in POLG 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.

[0025] In one embodiment, the MDDS disorder characterized by a mutation in POLG 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.

[0026] In one embodiment, the subject to be treated is: (a) a pediatric patient less than 12 years old; (b) an adolescent over an age of 12 years old through an adult up to age 40; or (c) an adult over age 40.Attorney Docket No. PTZ-011WO

[0027] 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 having a structure of 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;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 groupAttorney Docket No. PTZ-011WOconsisting of F, Cl, OR5, CN, C1-C4 alkyl, and NR5R5, (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)-U7-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)-l / 7-pyrazol-3-yl)urea, is excluded.Attorney Docket No. PTZ-011WO

[0028] 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 having a structure of formula (II):RsFormula (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(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;R7 is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2ORe;Attorney Docket No. PTZ-011WOn is 1-4; and*denotes a chiral carbon.

[0029] 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 having a structure of formula (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,Attorney Docket No. PTZ-011WONH-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 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, 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(5)-l-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2Z7-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.Attorney Docket No. PTZ-011WO

[0030] 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 having a structure of formula (IV):y3^Y2Formula (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.

[0031] 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 having a structure of formula (V):s OvZ' JL JI. AN NV H HFormula (V)wherein:Attorney Docket No. PTZ-011WOA 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.

[0032] In one embodiment, the compound has a structure of formula (I), (II), (III), (IV), or (V), or is a compound in any of Table 1, Table 2, Table 3, Table 4, or Table 5.

[0033] 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

[0034] FIG. 1A graphically shows the classification of primary mitochondrial disorders (PMDs), and supports the premise 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 mutation in mitochondrial diseases, such as PMD. The next category is mtDNA Depletion Syndromes (MDDS), 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 and deletions in mtDNA lead to >70% of PMD.

[0035] FIG. IB shows known pathogenic mutations of POLy that may cause PMD and / or MDDS. Exemplary PMD and / or MDDS disorders are listed at the bottom of the figure.

[0036] FIG. 1C shows the nominal location of common mutations, A467T, W748S, and G848S, along the POLG functional genome.

[0037] FIG 2A identifies exemplary specific POLy mutations common in many PMD and / or MDDS patients: A467T, W748S, G848S, T251I-P587L. Data shown in FIG. 2B shows that compounds described herein activate a wide range of mutated POLy (e.g., A467T,Attorney Docket No. PTZ-011WOG848S, W748S, R309C, and Y955C), with the graph shown depicting the processivity of the mutated form of POLy as a % of WT activity vs Log10concentration (pM).

[0038] FIG. 3 shows data demonstrating that multiple compounds described herein (Cl, C2, C3, C4 and C5), each at 50 nM, result in an increase in mtDNA in A467T / G848S (first bar in each pair) and W748S + El 143G / R232H (second bar in each pair) mutants in patient-derived fibroblasts as compared to a control.

[0039] FIGs. 4A-C show that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea) bind specifically to POLy, as measured by thermal shift assays. FIG. 4A shows a POLy WT Thermal Shift Assay of Relative fluorescence unit (RFU) (normalized) vs temperature (°C) of wild type (WT) and WT + l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea, in patient-derived fibroblasts. FIG. 4B shows a POLy mutant Thermal Shift Assay of RFU (normalized) vs temperature (°C) of mutant G848S and mutant G848S + l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea, in patient-derived fibroblasts. FIG. 4C shows the results of a POLy WT thermal shift assay of Fluorescence (norm) vs temperature (°C) for dimethylsulfoxide (DMSO) and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea.

[0040] FIG. 5 shows a graph of ethidium bromide (EtBr)-depleted proliferating cells (WT), 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 do not show a different recovery speed of mtDNA when treated with DMSO (control) and 1 pM concentration of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea.

[0041] FIGs. 6A-D show that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea) accelerate mtDNA recovery in quiescent WT and POLy mutant fibroblasts. T7: 7-day depletion in proliferation phase; T7+3: 7-day depletion in proliferation phase and 3-day recovery in quiescent phase; and T7+T3: 7-day depletion in proliferation phase and 3-day depletion in quiescent phase. FIG.6A shows EtBr depletion in proliferation phase for WT T7 +3 quiescent, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-Attorney Docket No. PTZ-011WOhydroxyethyljthi azol -4-yl )urea at 1 pM and DMSO. FIG. 6B shows EtBr depletion in proliferation phase for A467T / G848S T7+3 quiescent, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea at 1 pM (repeated twice), and DMSO (repeated twice). FIG.6C shows EtBr depletion in proliferation and quiescent phase for WT T7 + T3, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea at 1 pM (repeated twice) and DMSO (repeated twice). FIG. 6D shows EtBr depletion in proliferation and quiescent phase for A467T / G848S T7+3 quiescent, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea at 1 pM (repeated twice), and DMSO (repeated twice). Quiescent WT cells show recovery of mtDNA regardless of DMSO or compound treatment after 7-day depletion in proliferation phase, but more recovery of mtDNA when treated with compound, after a total of 10-day depletion. Quiescent A467T / G848S cells show more recovery of mtDNA when treated with compounds after 7-day depletion in proliferation phase, but no recovery of mtDNA at all after a total of 10-day depletion.

[0042] FIGs. 7A & B demonstrate that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea) accelerate mtDNA recovery in a concentration dependent manner. T7: 7-day depletion in proliferation phase, and T7+T3: 7-day depletion in proliferation phase and 3-day depletion in quiescent phase. FIG. 7A shows a graph of EtBr-depleted quiescent cells, time course and dose response, for W748S+E1143G / W748S+E1143G mutants (patient derived fibroblasts), with mtDNA / nDNA normalized to undepleted vs l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea concentration, for 5, 15, and 21 days, and FIG. 7B shows a graph of EtBr-depleted quiescent cells, time course and dose response, for T251I+P587L / W748S+E1143G mutants (patient derived fibroblasts), with mtDNA / nDNA normalized to undepleted vs l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea concentration, for 5 and 15 days. After a ten-day depletion, both W748S+E1143G / W748S+E1143G and T251I+P587L / W748S+E1143G have a dose dependent recovery of mtDNA after 15 -day or 21 -day treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol -4-yl)urea.Attorney Docket No. PTZ-011WO

[0043] FIG. 8 shows a biochemical activity assay for l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea, with a graph of mtDNA recovery response vs 1 -((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea concentration in POLy patient fibroblasts (A467T, G848S, and W748S). ACso (pM) for A467T, G848S, and W748S was 2.58, 0.438, and 0.442, respectively, and Max activation (WT ratio) for A467T, G848S, and W748S was 0.75, 0.95, and 0.65, respectively.

[0044] FIGS. 9A-D show that l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea accelerates mtDNA recovery in a concentration-dependent manner. Data is for EtBr depleted quiescent cells. Treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea over 7- or 14-days showed a dose-dependent acceleration of mtDNA recovery in quiescent A467T / G848S (FIG. 9A),W748S+E1143G / R232H (FIG. 9C), and G303R / A467T (FIG. 9D) mutant fibroblasts. In quiescent A467T / A467T fibroblasts (FIG. 9B), the DMSO control recovered to baseline within 14-days, but treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea still showed a trend of increased mtDNA levels after recovery.

[0045] FIGs. 10A-C demonstrate that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea) increase mtDNA copy number in POLG mutant fibroblasts. Three quiescent POLy mutant fibroblasts show better recovery of mtDNA when treated with l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea vs DMSO control. T7: 7-day depletion in proliferation phase; and T7+3: 7-day depletion in proliferation phase and 3-day recovery in quiescent phase. Data was for EtBr-depleted quiescent cells, 2 time points (7 and 14 days). FIG. 10A shows results for the mutant fibroblast A467T / A467T, with mtDNA copy number measured for undepleted, T7, T7+3, DMSO at day 7, l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea (1 pM) at day 7, DMSO at day 14, and l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea (1 pM) at day 14. FIG. 10B shows results for the mutant fibroblast A467T / G848S, with mtDNA copy number measured for undepleted, T7, T7+3, DMSO at day 7, 1 -((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea (1 pM) at day 7, DMSO at day 14, and l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-Attorney Docket No. PTZ-011WOhydroxyethyljthi azol -4-yl )urea (1 pM) at day 14. FIG. IOC shows results for the mutant fibroblast W748S + El 143G / R232H, with mtDNA copy number measured for undepleted, T7, T7+3, DMSO at day 7, compound (1 pM) at day 7, DMSO at day 14, and compound (1 pM) at day 14.

[0046] FIGS. 11A-D show that l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea accelerates mtDNA recovery in human fibroblasts harboring POLy mutations. l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea exhibited dose-dependent acceleration of mtDNA recovery post EtBr depletion in POLy patient fibroblasts in both screening and small-scale validation experimental paradigms. The graphs show EtBr depleted proliferating cells, dose response. FIG. 11A shows a graph of screening data for A467T / G848S, with normalized mtDNA levels (to DMSO) vs compound concentration (pM). FIGS. 11B-D show small scale validation data. FIG. 11B shows a graph of mtDNA copy number per cell for the mutant A467T / G848S for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.01 pM, 0.03 pM, 0.1 pM, and 1 pM. FIG. 11C shows a graph of mtDNA copy number per cell for the mutant W748S + El 143G / R23H for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.01 pM, 0.03 pM, 0.1 pM, and 1 pM. FIG. 11D shows a graph of mtDNA copy number per cell for the mutant A467T / A467T for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.01 pM, 0.03 pM, 0.1 pM, and 1 pM.

[0047] FIGs. 12A-C demonstrate that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea) accelerate mtDNA recovery in quiescent POLy mutant fibroblasts. The graphs show EtBr depleted, quiescent fibroblasts at 2 time points (7 and 14 days). Collectively, the data shows that quiescent or non-mitotic conditions exacerbate mtDNA recovery phenotypes in patient fibroblasts. FIG.12A shows a graph of mtDNA copy number per cell for the mutant POLy G737R / R232H fibroblasts for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.1 pM (7 days), 1 pM (7 days), 0.1 pM (14 days, and 1 pM (14 days). FIG. 12B shows a graph of mtDNA copy number per cell for the mutant POLy G737R / R232H fibroblasts for each of non-depleted, +EtBr, DMSO, and l-((S)-8-Attorney Docket No. PTZ-011WOchlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.1 pM (7 days), 1 pM (7 days), 0.1 pM (14 days, and 1 pM (14 days) (repeat of the experiment for FIG 9A). FIG. 12C shows a graph of mtDNA copy number per cell for the mutant POLy F197S / T914P fibroblasts for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 1 pM (7 days), and 1 pM (14 days).

[0048] FIG. 13 shows that l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea increases mtDNA copy number in various differentiated POLy mutant DE cells (S-A467T / A467T, R-A467T / A467T, R-W748S / W748S, and WT). The graphs depict mtDNA copy number vs DMSO and 1 pm l-((S)-8-chlorochroman-4-yl)-3 -(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea for each of the different mutant cell types and WT.

[0049] FIGS. 14A-D show that l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea increases mtDNA in human iPSCs and definitive endoderm.5-day treatment of 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea significantly increases mtDNA level in G848S / G848S (FIG. 14A) and A467T / A467T iPSCs (FIG. 14C). 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol -4-yl)urea restores mtDNA levels to WT levels during definitive endoderm differentiation (DE) towards hepatocytes (FIG. 14B). Combination treatment of 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea and standard supplements increases %cell number and restores defective DE differentiation in mutant A467T / A467T iPSCs to wildtype levels (FIG. 14D).

[0050] FIGS. 15A-C show that G848S / G848S NSCs have a respiration deficiency, rescued by 1 -((S)-8-chlorochroman-4-yl)-3 -(2-((S)- 1 -hydroxy ethyl)thiazol-4-yl)urea.G848S / G848S homozygous cell line is respiration deficient over the 10-day time course. No dose response between 1 & 3 pM of the compound, the timepoints are similar. OCR = oxygen consumption rate = oxygen flux; ECAR = extracellular acidification rate = proton flux. FIG. 15A shows that G848S / G848S NSCs have a respiratory deficit when compared to WT NSCs, with the graph depicting OCR (pmol O2 / min / 103cells vs time (minutes) (5, 7 and 10 days), for DMSO and WT. FIGs. 15B and 16C show that improvements in cellular energetics are observed by 5-days of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-Attorney Docket No. PTZ-011WOhydroxyethyl)thiazol-4-yl)urea treatment, with FIG. 15B showing the oxygen consumption rate at day 5 (OCR (pmol O2 / min / 103cells) vs time (minutes), for DMSO and compound at 1 and 3 pM, and FIG. 15C showing the extracellular acidification rate at day 5 of compound treatment (ECAR (mpH / min / 103cells) vs time (minutes), for DMSO and compound at 1 and 3 pM.

[0051] FIGS. 16A-C show that l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea increases mtDNA and basal respiration in G848S / G848S NSCs. Treatment with 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea improves respiration after 7 days, results are consistent with 10-day treatment. Lower concentrations show improvements in cell morphology but no significant respiratory improvement. l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea-treated NSCs demonstrate improvements in cellular energetics, following 7-days of treatment. FIG. 16A shows a graph of oxygen consumption rate - day 7, with OCR (pmol / min / 104cells) vs time (minutes) for each of WT, DMSO, 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM, and 1 pM of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea. FIG. 16B shows the basal respiration 7 day, with OCR (pmol / min / 104cells) for each of WT, DMSO, 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM, and 1 pM of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea. FIG.16C shows that l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea -treated NSCs have higher mtDNA, with the graph depicting mtDNA 7-day, with mtDNA level (normalized to WT) for each of WT, DMSO, 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM, and 1 pM of compound. This data demonstrates that G848S / G848S NSCs have a respiration deficiency, which can be rescued by the compounds described herein (e.g., 1-((S)-8-chlorochroman-4-yl)-3 -(2-((S)- 1 -hydroxyethyl)thiazol-4-yl)urea).

[0052] FIG. 17A & B show that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea) enhance cellular respiration. POLG G848S mutant neural stem cells treated with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea increases basal and ATP -Linked oxidative phosphorylation, with improved cellular respiration (FIG. 17A = basal respiration) andAttorney Docket No. PTZ-011WOenergy production (FIG. 17B = ATP production rate) following treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea.

[0053] FIGs. 18A-E show that the compounds described herein enhance cellular respiration (increases in mtDNA and respiration in POLy patient fibroblasts). FIGS. 18A & B show that (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea improves mtDNA recovery following depletion. FIG. 18A shows that for mutant A467 / G848S patient fibroblasts, (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea produced a significant increase in mtDNA levels, demonstrating mtDNA recovery following depletion.FIG. 18B shows similar results for the mutant W748S / R232H patient fibroblasts. FIGS. 18C & D show that (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea increases cellular respiration for the A467 / G848S and W748S / R232H mutant patient fibroblasts, including both basal respiration (FIG. 18C) and maximal respiration (FIG. 18D). FIG. 18 shows that (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea shifts ATP production rate to favor OXPHOS, for the A467 / G848S and W748S / R232H mutant patient fibroblasts.

[0054] FIGS. 19A & B show brightfield images of representative S-G848S / G848S induced pluripotent stem cells (iPSCs). Treatment with the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea) supports differentiation of POLy cells from iPSCs to hepatocytes (Compound treatment improves iPSC viability and cellular morphology). FIG. 19A shows S-G848S / G848S control, with low viability and poor cellular morphology; hepatocyte differentiation not viable. FIG. 19B shows S-G848S / G848S + 100 nM compound, where cell viability is greatly improved, and the compound appears to recover hepatocyte differentiation potential.

[0055] FIGs. 20A-B show that compound C9 and compound C12 increase mtDNA recovery in A467T / G848S fibroblasts in a concentration-dependent manner. Treatment with compound C9 at concentrations of 0.0001 pM, 0.001 pM, 0.01 pM, 0.1 pM, and 1 pM (FIG.20A) and compound C12 at concentrations of 0.0001 pM, 0.001 pM, 0.01 pM, 0.1 pM, and 1 pM (FIG. 20B) showed a dose-dependent increase of mtDNA recovery in quiescent POLG A467T / G848S mutant fibroblasts. Compound 5360 at 1 pM was included as a reference control.Attorney Docket No. PTZ-011WO

[0056] FIGS. 20C-D show that compounds C9 and C12 increased mtDNA copy number in POLG W748S+E1143G / R232H mutant fibroblasts. FIG. 20C shows treatment with compound C9 at concentrations ranging from 0.0001 pM to 1 pM, and FIG. 20D shows treatment with compound C12 at concentrations ranging from 0.0001 pM to 1 pM. Both compounds demonstrated statistically significant increases in mtDNA levels compared to DM SO control.

[0057] FIG. 20E shows mtDNA recovery in POLG W748S+E1143G / M1163R mutant fibroblasts. 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea (C7) and 1 or 0.1 pM (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 (C13) demonstrated statistically significant higher mtDNA copy number over 7 days of treatment (FIG. 20E).

[0058] FIG. 20F demonstrates mtDNA copy number recovery in POLG A467T / R574W mutant fibroblasts. Treatment with C6 at 0.1 pM and 1 pM was compared to DMSO control.0.1 or 1 pM C6 yielded statistically significantly higher mtDNA copy number over 7 days of treatment.

[0059] FIG. 20G shows mtDNA copy number recovery in POLG G737R / R232H 1 mutant fibroblasts. Treatment was evaluated at Day 7 and Day 14. Cells were treated with compound C7 at 1 pM, compound C 13 at 1 pM, and compound C13 at 0.1 pM. A statistically significant increase in mtDNA copy number was after 7 days of treatment.

[0060] FIG. 20H shows mtDNA copy number recovery in POLG Y955C mutant fibroblasts. Treatment with compound C7 at 0.1 pM and 1 pM, and compound 5360 at 0.1 pM and 1 pM showed concentration-dependent increases in mtDNA levels compared to DMSO control.

[0061] FIG. 201 shows mtDNA copy number recovery at Day 7 and Day 14 following T3 depletion and T3+3 recovery phases. Treatment with compound 5360 at 1 pM, compound C8 at 1 pM, compound CIO at 1 pM, and compound Cl 1 at 1 pM was compared to DMSO control. A positive control of 50 pM dN+EHNA was included. Statistically significant effects were observed after 14 days of treatment.Attorney Docket No. PTZ-011WO

[0062] FIG. 21 shows relative mtDNA copy number (normalized to DMSO) in wild-type in POLG G848S / G848S mutant cells treated with compound C9 at various concentrations.

[0063] FIG. 22 demonstrates mitochondrial respiration measured by oxygen consumption rate (OCR) in pmol / min / 3 * 104cells in POLG G848S / G848S mutant NSCs over time.

[0064] FIG. 23 shows maximal respiration measured by OCR (pmol / min / 3 * 104cells) in POLG G848S / G848S mutant NSCs treated with DMSO control or compound C9 at concentrations of 0.00001 pM, 0.0001 pM, 0.001 pM, 0.01 pM, 0.1 pM, and 1 pM.Statistically significant dose-dependent increases in maximal respiration were observed.

[0065] FIG. 24 demonstrates basal respiration measured by OCR (pmol / min / 3 *104cells) in wild-type cells treated with DMSO control or compound C9 at concentrations of 0.00001 pM, 0.0001 pM, 0.001 pM, 0.01 pM, 0.1 pM, and 1 pM. Statistically significant dosedependent increases in basal respiration were observed.

[0066] FIG. 25 shows relative mtDNA levels measured on days 7-28 in wild-type (WT) and R-W748S mutant cells with or without 1 pM C6 treatment.

[0067] FIG. 26 demonstrates oxygen consumption rate (OCR) measured in fmol / mm2 / s / ng DNA on day 28 in wild-type and R-W748S mutant cells with or without 1 pM C6 treatment. OCR was measured in WT cells with DMSO, R-W748S mutant cells with DMSO, and R-W748S mutant cells with 1 pM C6.DETAILED DESCRIPTIONI. Overview

[0068] The present disclosure is directed, in part, to 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 some embodiments, the disease or disorder is a Mitochondrial DNA Depletion Syndrome (MDDS). In some embodiments, the method comprises a subject diagnosed with, or at risk of developing, a PMD or MDDS disorder; and administering a therapeutically effective amount of a compound as described herein, where the subject has one or more mutations or deletions in the DNA polymerase y gene (POLG).Attorney Docket No. PTZ-011WO

[0069] Primary mitochondrial diseases (PMDs)

[0070] Primary mitochondrial diseases (PMDs) are a heterogeneous group of genetic disorders caused by dysfunction of the mitochondria, which is responsible for energy production 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.

[0071] 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

[0072] Classical mitochondrial syndromes include Leigh syndrome (subacute necrotizing encephalomyelopathy), mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), myoclonic epilepsy with ragged-red fibres (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.

[0073] 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.Attorney Docket No. PTZ-011WO

[0074] 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 Charcot-Marie-Tooth disease type 2A (CMT2A) caused by MFN2 mutations and dominant optic atrophy (DOA) caused by OPA1 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.

[0075] Mitochondrial DNA Depletion Syndrome

[0076] At present, there are no effective drug treatments for mitochondrial DNA depletion disorders (MDDS). MDDS refers to autosomal recessive disorders and autosomal dominant disorder 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.1A shows a classification of primary mitochondrial disorders into the following categories: mtDNA mutation and / or deletion syndromes, mtDNA depletion syndromes, and POLy mutations.

[0077] 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 POLy are the most common cause of inherited mitochondrial disorders, with as many as 2% of the population carrying these mutations, and more than 300 pathogenic mutations of POLy have been reported (FIG. IB).The most common mutations include A467T, W748S, and G848S, which are found in 70% of all patients and have a combined carrier frequency of over 1% in Northern Europe (FIG.1C). POLy-related disorders comprise a continuum of overlapping phenotypes with onset from infancy to late adulthood. Six disorders caused by POLy mutations are Alpers-Huttenlocher syndrome, which is has severe phenotypes; childhood myocerebrohepatopathy spectrum, which presents within the first 3 years of life; myoclonic epilepsy myopathyAttorney Docket No. PTZ-011WOsensory ataxia; ataxia neuropathy spectrum; autosomal recessive progressive external ophthalmoplegia; and autosomal dominant progressive external ophthalmoplegia.

[0078] Mitochondrial DNA polymerase y (POLy) is essential for replicating the mitochondrial genome. Over 300 mutations in this gene have been linked to severe, progressive conditions with high rates of morbidity and mortality. In particular, mutations in POLG are associated with numerous clinically heterogeneous syndromes characterized by a quantitative and / or qualitative mtDNA defect. Seizures dominate the clinical picture, not only in childhood-onset cases, but also in POLG-related disease presenting in early adult life and in the adult ataxic forms of the disease, indicating a poor prognosis. Other disease manifestations include ataxia, movement disorders, PEO, myopathy and peripheral neuropathy, as well as multisystem features such as cataracts, cardiomyopathy, premature menopause and gastrointestinal pseudo-obstruction. Despite tremendous advances in mitochondrial disease diagnostics in recent years, effective disease-modifying therapies are still lacking.

[0079] POLG activators

[0080] The present disclosure describes small molecules categorized as activators of mtDNA synthesis, capable of restoring function to disease-causing variants of POLy. The compounds restore wild-type-like activity to mutant POLy in vitro and activate mtDNA synthesis in cells from patients, such as pediatric patients, with lethal POLG disease, thereby enhancing biogenesis of the oxidative phosphorylation machinery and cellular respiration. This remarkable gain-of-function mechanism demonstrates the usefulness of the compounds in treating mutant POLG disorders.

[0081] POLy (e.g., POLG) is composed of a 140 kDa catalytic subunit that is encoded by POLG at chromosomal locus 15q25, and a 55 kDa accessory subunit that forms a dimer and is encoded by POLG2 at chromosomal locus 17q24.14-6, collectively the “POLG gene”. POLy has DNA polymerase, 3’ to 5’ exonuclease and 5 ’-deoxyribose phosphate (5’-dRP) lyase activities (UniProt ID P54098). This subunit contains an amino-terminal exonuclease domain connected by a linker region to the carboxy -terminal polymerase domain. POLy2 enhances polymerase processivity by increasing the affinity of the catalytic subunit for DNA (UniProt ID Q9UHN1). In some embodiments, POLG genomic sequence is NCBI ref:Attorney Docket No. PTZ-011WONG_008218.2, and mRNA sequence is NM_001126131.2. In some embodiments, POLG2 genomic sequence is NCBI ref: NG_013029.2, and mRNA sequence is NM_007215.4.

[0082] Experimental Data: Data described herein demonstrates the effectiveness of POLg activators (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 patient cells. The positive results are not limited to a specific POLy mutation or a specific cell type. For example, FIG. 3 shows data demonstrating that multiple compounds described herein result in an increase in mtDNA in two different POLy mutants, and FIGs. 10A-C and FIG. 13 demonstrate that the compounds described herein increase mtDNA copy number in POLy mutant fibroblasts. In some embodiments, low mtDNA levels are a cause of PMD and MDDS disease presentation and progression, and therefore restoring mtDNA leads to improvements in patient cellular function. FIGs. 12A-C demonstrate that treatment with compounds described herein accelerates mtDNA recovery relative to a control for different exemplary POLy mutants. FIGs. 6A-D and FIGS. 11A-D show that the compounds described herein accelerate mtDNA recovery POLy mutant fibroblasts, and FIGs. 7A & B, FIGS. 11A-D, and FIGS. 9A-D demonstrate that the compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea) accelerate mtDNA recovery in a concentration dependent manner. FIGS. 14A-D show that compounds described herein increase mtDNA in human iPSCs and definitive endoderm. FIGS. 16A-C show that POLy mutants having a respiration deficiency are rescued by compounds described herein, and treatment results in improvement in cellular energetics, including oxygen consumption rate and extracellular acidification rate. Further, FIGS. 17A-C show that compounds described herein increase mtDNA and basal respiration in POLy mutants, and FIG. 18A & B and FIGs. 19A-E show that the compounds described herein enhance cellular respiration in POLy mutants. Finally, FIGS. 20 A & B show data demonstrating that treatment with compounds described herein supports differentiation of POLy cells from iPSCs to hepatocytes, and treatment improves iPSC viability and cellular morphology.II. Methods

[0083] 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 aAttorney Docket No. PTZ-011WOPrimary Mitochondrial Disorder (PMD). In another aspect, provided herein are methods of treating MDDS in a subject in need thereof. In some embodiments, the method comprises identifying a subject diagnosed with, or at a risk of developing, a PMD or MDDS disorder, 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 has one or more mutations or deletions in the DNA polymerase y gene (POLG).

[0084] In one aspect, the compound is a compound 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) US Provisional Application No.62 / 676,628, filed July 29, 2024, titled Modulators of Mitochondrial DNA Replication, (4) US Provisional Application No. 63 / 637,658, filed April 23, 2024, titled Modulators of Mitochondrial DNA Replication, and / or (5) US Provisional Application No. 63 / 696,121, filed September 4, 2024, titled Modulators of Mitochondrial DNA Replication, which are incorporated by reference.

[0085] 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;Attorney Docket No. PTZ-011WOR3is 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)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, and NR5R5, (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;Attorney Docket No. PTZ-011WOR7is 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, 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;with the proviso that a compound selected from the group consisting of:l-(l,5-dimethyl-l / 7-pyrazol-3-yl)-3-(8-methylchroman-4-yl)urea,l-(8-methylchroman-4-yl)-3-(l-(l-methylpiperidin-4-yl)-U / -pyrazol-3-yl)urea,l-(l-(2-(dimethylamino)ethyl)-l / 7-pyrazol-3-yl)-3-(8-fluorochroman-4-yl)urea,l-(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, is excluded.

[0086] In some embodiments, a compound of formula 1 is identified in Table 1:Table 1Chemical Name Structure(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(4- cy anophenyl)- 1 / 7-py razol -3 -yl)urea 1 l[ jL,14 (\ / / — -SN 1... / 8 J H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- o-A 0methoxypyridin-4-yl)-lJ / -pyrazol-3- cu A A JI Ayl)urea "-r N" " N' A,~Nif H HAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(3 - N cyanophenyl)- 1 / / -py razol -3 -yl)ureaCl....?Z X] PAAAH H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- tr""x1 0 fiSSA. --N (dimethylamino)ethyl)-l / / -pyrazol-3- Cl.... 1 H kN-z'■■■< yl)urea%N| ■ N '" AH H(5)-4-(3-(3-(8-chlorochroman-4- 0'A0\ yl)ureido)- 1 / / -pyrazol - 1 -yl)-N, N- Vri: A A A A AAA A" dimethylbenzamide t.... JH Hb (5)-4-(3-(3-(8-chlorochroman-4- o ' QNHyl)ureido)- 1 / / -pyrazol - 1 -yl)benzamide 1ci.... j. i Ln ■H H(5)- 1 -( 1 -(4-(2-aminopropan-2- yl)phenyl)- lJ7-pyrazol-3 -y l)-3 -(8-chloro-? AAA NH2Ck. A. X / A A. / N\\ / ) — £— 5 -fluorochroman-4-yl)urea V AxN IM N XL V j| J H H1 -( 1 -ethyl- 1 / / -py razol -3 -y 1 ) -3 -(8- fluorochroman-4-yl)urea 0 XN / A. A. A AH Hl-((5)-8-chlorochroman-4-yl)-3-(l-(4- (4,4-difluoropyrrolidin-2-yl)phenyl)-l / / - Cl,.pyrazol-3-yl)urea'-A F l-((5)-8-chlorochroman-4-yl)-3-(l-(4- o A o IJ (4,4-difluoropyrrolidin-2-yl)phenyl)-l / / - Ch,.. 1 J. I k w A / S pyrazol-3-yl)urea il 1 H 11F1 -[ 1 - [4-( 1 -aminocyclopropyl) phenyl]pyrazol-3-yl]-3-[(45)-8-chlorochroman- Ck X ) jj HA NL 4-yl]urea ¥ X " N"' X: L Y H H ■■■"i"-'"Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- 0F[2-(dimethylamino)-l, 1 -difluoro- ci... I A. N-x i.. J ethyl ]pheny 1 ] py razol -3 -y 1 ]urea N ' N '" A V / \ / H H - 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4-? A o [(l-(dimethylamino)ethyl] phenyl] Ck, K X, A pyrazol-3-yl]urea A I / Us H ' " N X. / "'A AHQ.--X 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- 0 - ’■■ [(l-(dimethylamino)ethyl] phenyl] ci..... L Y Y A Y pyrazol-3-yl]ureaH H ’KIJ1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 -Cl? i t AA [1 -methyl- 1 -(methylamino)ethyl]phenyl] pyrazol-3-yl]urea<,.x,,..-p-Mi 0 r-isA l-[l-[4-(azeti din-3 -yl) phenyl] pyrazol- (A< M XJ'Kx 3-yl]-3-[(45)-8-chlorochroman-4-yl]urea CC Y x -'N- N:H H VF 2-(3 -(3 -(8-fluorochroman-4-yl)ureido)- 1 / / -py razol - 1 -yl)-N, N-,x...0-.dimethylacetamide0 / H HIMS„ N.„01 -[ 1 - [4-(3 -aminooxetan-3 -yl)phenyl] O AAA pyrazol-3-yl]-3-[(45)-8-chlorochroman- 1.1 A... A £ vAA 4-yl]urea A (J1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- 0[l-methylpyrrolidin-2-yl] phenyl] OAAJS Ck,A' ] ’ N ' h. pyrazol-3-yl]ureaH 11 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- 0[l-methylpyrrolidin-2-yl] phenyl] L A / AYS Ck, •• A' \A \ / ’ N ' '" F. pyrazol-3-yl]ureaH 1Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- O’z[1 -methyl- 1 -(methylamino) ethyl] Cl...... jt •*- phenyl] pyrazol-3-yl]urea AC N " ' NH Hf1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- oA 0 Ay.(l-methylazetidin-3-yl)phenyl]pyrazol- AA k 'N AAA • / >- 3-yl]ureackI. JhH1 -[ 1 - [4-( 1 -amino- 1 -methyl-ethyl)-3 - fluoro-phenyl ] py razol -3 -y 1 ] -3 - [(45)- 8 - A C k.. ZMHchlorochroman-4-yl]urea T J 'M'~ N % / / \ NHg1 H" V r ' 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- O'""k[2-(dimethylamino)acetyl] ck„ A.■ W V / phenyl]pyrazol-3-yl]urea J; r " N- ’ NI \\ z? ' \A i H1 -[ 1 -[3 -fluoro-4-(2-,.FOH hydroxyethylamino)phenyl]pyrazol-3- Ac y _ z yl]-3-[(45)-8-chlorochroman-4-yl]urea 'T r N N1 i- I H1 -[ 1 - [6-( 1 -amino- 1 -methyl-ethyl)-3 - pyridyl]pyrazol-3-yl]-3-[(45)-8- J, A fU / A / chlorochroman-4-yl]urea p Y A" tr A AAAM, A AHHH'■ 1 - [ 1 - [4- [ 1 -amino-2,2,2-trifluoro- Oethy 1 ]pheny 1 ] py razol -3 -y 1 ] -3 - [ ( 4*8) - 8 - cixA J., A J. N— / \ NH2chlorochroman-4-yl]urea TI A'' 'N N' Al' V / / ~~\* M V- F F F1 - [ 1 - [4- [ 1 -amino-2,2,2-trifluoro- ethy 1 ]pheny 1 ] py razol -3 -y 1 ] -3 - [ ( 4*8) - 8 - chlorochroman-4-yl]urea A AV A Ar N'NA VAA 7*NH2AFF'F1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- ® N,..[pyrrolidin-2-yl] phenyl] pyrazol-3- CU... A A.:NA A--4 i yl]urea ■’N' N' N \ _ j H HAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- n. _ H [pyrrolidin-2-yl] phenyl] pyrazol-3- a... Y..yl]urea Y ' ” " M ” N W / "... J 1 J H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- [2-(dimethylamino)ethyl]? U X rxA A^. A^s 9 / / ••■■-■•z / -< x phenyl]pyrazol-3-yl]urea '■Y ”N"' " N: V.yH H1 -[ 1 - [4-( 1 -amino- 1 -methyl- O'"’ 0 fY / ethy l)pheny 1 ] py razol -3 -y 1 ] -3 - [chroman- Y A A AA'A Y— YNH-? 4-yl]ureax AH H1 -[ 1 - [4-( 1 -amino- 1 -methyl- 9" A 9 XA. / ^\ / ethy l)pheny 1 ] py razol -3 -y 1 ] -3 - [chroman- A A.9. Ay 9 — O-'NH- 4-yl]ureaJ H Hl-[(45)-8-chlorochroman-4-yl]-3-(l- phenylpyrazol-3-yl)urea (C8) Cl J- X y. N-Y Ay j N ’ Y"” 'Y' V XH H ' l-[(45)-8-fluorochroman-4-yl]-3-(l- 0 " N >phenylpyrazol-3-yl)urea F,.,1 J 0 I M... A 3)Y h J 1 y H M H N y(S)- 1 -(8-fluorochroman-4-yl)-3 -( 1 - O' A Ophenyl - lH-pyrazol-3 -yl)urea fx ■y Ay j '■"f N H H '••-A 31 -[ 1 - [4-( 1 -amino- 1 -methylethyl) 0 z-Tx-- phenyl]pyrazol-3-yl]-3-[(45)-8- 0 L XA A / chlorochroman-4-yl]urea H HKl-[(45)-8-methylchroman-4-yl]-3-(l- 0phenylpyrazol-3-yl)urea ’’YAXA'-. A A Y-Y 9i' J H H A / 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3 - A"' ' I o _ / fluorophenyl) pyrazol-3-yl] ureaCI\A 9'. J J- 9( T H H "NA?Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure1 -[ 1 -(3 -fluorophenyl) pyrazol-3 -y 1 ] -3 - " i 0 ' [(45)- 8 -methyl chroman-4-y 1 ]urea J.. 1 X N-Y ’II J k * w1 -[ 1 - [4-( 1 -amino- 1 -methylethyl) oY 0 _ phenyl]pyrazol-3-yl]-3-[(45)-8- K., Z A 11 t. N-Y Y NHz fluorochroman-4-yl]urea A N' 'N " " N ZZ \. A H H! " 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(6- O" > O r=A z^-. methoxy-3-pyridyl)pyrazol-3-yl]urea [ 1; i„ N— XCks] J H H ’l-[(45)-8-chlorochroman-4-yl]-3-(l- 0tetrahydropyran-4-ylpyrazol-3-yl)urea CK..v1 1 1L A' 'NH UH3-[3-[[(45)-8-chlorochroman-4- y 1 ] carb amoy 1 amino] py razol - 1 - yl]benzamide O '" A O AAr-| 1 J. U k M~ YV "N' ”'N' °H J H H1 -[ 1 -[4-[2-(dimethylamino)oyo ethoxy]phenyl]pyrazol-3-yl]-3-[(45)-8- ci.. X J J L A. / ■ — chlorochroman-4-yl]ureaX J k ■ ' LA- 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- O'""'--; 0 - F [1, l-difluoro-2- (methylamino)ethyl] CL.,-L. J.. A 4 XJY phenyl] pyrazol-3 -yl]urea X '-Y' 'fN ' N' N - X \ H5 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - [2-(methylamino)ethoxy] 0--zphenyl]pyrazol-3-yl]urea o r-A, Z~AII j N -A \C!x, X J- ''A -'N- ""'•Y Y W; HAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure l-(8-chloro-2-(methoxymethyl)chroman- A 4-yl)-3-(l-phenyl-U7-pyrazol-3-yl)urea i ii A V' 9 s >o - / -x■ 9? O / 'i-•l-(8-chloro-2-(methoxymethyl)chroman- _ \ ( o,\ - / * I4-yl)-3-(l-phenyl-U7-pyrazol-3-yl)urea A oO' Oo o ClxJ- *1 ll N-A \\ T[': N N V 1 Y H Hl-[8-chloro-2-(hydroxymethyl)chroman- JDH4-yl] -3 -( 1 -phenylpyrazol -3 -yl)ureaZ—A Y Y N N N< AH Hl-[8-chloro-2-(hydroxymethyl)chroman- ^OH4-yl] -3 -( 1 -phenylpyrazol -3 -yl)urea9 H0Z-A ck A A A A \ Y A 'N N N V / (I J H Hl-[(45)-8-fluorochroman-4-yl]-3-[l-(3- A A oz._ / fluorophenyl) pyrazol-3-yl]urea K AA J.. Jl / ... N --:?9H 7 N' A ' Y 7 A AhHl-[8-chloro-2-(hydroxymethyl)chroman- 4-yl] -3 -( 1 -phenylpyrazol -3 -yl)ureaAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure l-[8-chloro-2-(hydroxymethyl)chroman-, OH4-yl] -3 -( 1 -phenylpyrazol -3 -yl)urea9' * '''] O r==\CK J. A X LV N N N V / ll J H H2-(3 -amino- 1 / 7-py razol - 1 -yl)-7V, N- 0 dimethylacetamide..., X. J. 0 k. A--- \ y '|f N ' ’ N ' '" WL V H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- G ”■ 9 \ h......[(dimethylamino)methyl] ci ^'N ' " N ""'N phenyl]pyrazol-3-yl]urea H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(2- Q’XX'methoxypyrimidin-5-yl) pyrazol-3- Ck..yl]urea H HN5-[3-[[(45)-8-chlorochroman-4- O'Xy 1 ] carb amoy 1 amino] py razol - 1 -y 1 ]-7V- Civ.. XA. >1 / .. N -. / \ NH methyl-pyridine-2-carboxamide ’IT 'H" % A—K HH“- N1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3 - methyl sulfonylphenyl) pyrazol-3-yl]ureaoClxH H4-[3-[[(45)-8-chlorochroman-4-yl] F carbamoyl amino]pyrazol-l-yl]-2-fluoro- O HN-— A-m ethyl -b enzami deW % j; J H M1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(2- 0methy 1 -4-py ri dyl)py razol -3 -y 1 ]urea CkvAN A "' 'N t Z'NH H:X. JAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 - A" 7 0-~- O(3,4-dimethoxyphenyl)pyrazol -3 -yl ]ureaCl -y'L.... J- JI L H -k / V ' A A \.....z'"0H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4- (J ■ 0 1.-Z, k pyridyl) pyrazol-3-yl]urea Cl 1 1.1 ' " N 'Lk AH'1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4- 0.... pyridyl) pyrazol-3-yl]urea a. 1 J jl A ' N A ATf 'N ' " A V Ab H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(3 - F fluoro-4-methoxyphenyl)- 1 / / -py razol -3 - o Ac. yl)urea A AJA 7-0 H Hl-[(45)-8-chlorochroman-4-yl]-3-(l- (A A 0 7k tetrahydropyran-4-ylpyrazol-3-yl)urea a.. A > - A AA'ANHt. J H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[ 1 - a A / \ / -OH (2 -hydroxy ethyl)-4-piperidyl]pyrazol-3- a... A -•1-v A o A' N N-^- yl]urea ip J H t1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(3 - cAApyridyl) pyrazol-3-yl]urea Ck.. A J *5! Vi..-Z N’’N”' ''A A A / Hi HA1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 - A'A F (3,4-difluorophenyl) pyrazol-3-yl]urea 0 AXCzvA... J X 4. N-A V..A' ''A AH H1 -[ 1 - [4-( 1 -amino- 1 -methylethyl)-2- 0 ' > 0. _fluoro-pheny 1 ] py razol -3 -y 1 ] -3 - [(45)- 8 - cu A J.. J A. NA 'A / chlorochroman-4-yl]urea Ti A N hT 'N A / / TNH,< AH H'Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(2- methyl sulfonylphenyl) pyrazol-3-yl]urea Q""X«... 1If 'I J f.|Hl-[(45)-5-fluorochroman-4-yl]-3-(l- u'" A o —?■. phenylpyrazol-3-yl)ureaV X N A? i J H H0.-^0F1 -[ 1 - [ 5 -( 1 -amino- 1 -methyl-ethyl)-2- pyridyl]pyrazol-3-yl]-3-[(45)-8- chlorochroman-4-yl]ureaX JHH1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(2- O"X'x0pyridyl) pyrazol-3-yl] cr... A.V H Hl-[(45)-7-fluorochroman-4-yl]-3-(l- o k—. phenylpyrazol-3-yl)urea A.. X. 1 L h-Afl V N • ’ N ’ -'" M' \ / ■. AHfS')-3 -(3 -(3 -(8-chlorochroman-4- Q yl)ureido)-l / 7-pyrazol- 1 -yl)-7V- oxA A-NH methylbenzamide Cl zssef il A N-A 1 'N ' " N " " N c. 4' H H(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)-l / 7-pyrazol- 1 -yl)-7V- Vi 2 r V / ;::A methylbenzamide (Cl)cSr'V -N ' W X / -A Ij J H H O fS')-3 -(3 -(3 -(8-chlorochroman-4- O yl)ureido)-l / 7-pyrazol- 1 -yl)-7V, N- A-N' dimethylbenzamide O”' "'•i 0 sO-A. / W \cr-.. A,■ H A H-A 1?iN'- 'IT N z_o H H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 - (4,4-difluorocyclohexyl) pyrazol-3- Ck A 1. 1 -a-, C hW << — / F yl]urea I J H HAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure (5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)-l / 7-py razol- 1 -yl)-7V, N- C)W dimethylbenzamide O"" X 0cu.x J., Ay "'V' '’fT A r' 'V \__x(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(4- p ««F / (trifluoromethoxy)phenyl)-l / / -pyrazol- Ck X i L w \ 3-yl)urea V V” 'X kA J " " N V,zC y J j b1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4- methyl sulfonylphenyl) pyrazol-3-yl]urea Cl%.-X z L.5 L % r r * wk- o1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[2- o'^X(hydroxymethyl)-2,3- X X vdCkyXX 'W Mdihy drob enzofuran-5 -y 1 ] py razol -3 - H Hyl]urea1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[2- ck N O.. W X'"" (hydroxymethyl)-2,3-CkyX^X.. A vd N h w / dihy drob enzofuran-5 -y 1 ] py razol -3 - H Hyl]urea(5)-4-(3-(3-(8-chlorochroman-4- o""k 0yl)ureido)- 1 / 7-py razol - 1 -yl)-7V- Cl., 1 J methylbenzenesulfonamide v X'"" "'f r w / '"-s -N y J *;. ■ H 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - H (m ethyl sulfamoyl) phenyl] pyrazol-3- a. ( / 9yl]urea ‘X J.i?X k / Wk H lr Ktk (5)-4-(3-(3-(8-chlorochroman-4- O^ Qyl)ureido)-l / 7-pyrazol-l-yl)-k,3- ck, X z Adimethylbenzamide ’X ■|S ■■ '" N " X f 0 V(l-[(45)-8-chlorochroman-4-yl]-3-[l-(4- CL. X methoxyphenyl)pyrazol-3-yl]urea □ / -:-k( bXF1Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- O'" k Ot-_-\(1 -hydroxy- 1 -methyl-ethyl) CL. X A it I- 1 pH phenyl]pyrazol-3-yl]urea If " N" F" o" FT VH H \ 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 - 0. f (2,2-difluoro-l,3-benzodioxol-5- O'"" -I o r-f yl)pyrazol-3 -yl]urea J.0 k V■-N-Nd - 'N \~.r / hl hl1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -( 1 - D"' 0 0 / ■"-'■'A methyl-4-piperidyl)pyrazol-3-yl]urea 1 k. N-k CL^XVor' '•'N" " N WH hl4-[3-[[(45)-8-chlorochroman-4- y 1 ] carb amoy 1 amino] py razol - 1 -y 1 ] -3 - fluor o-N -methyl -b enzami deX\ \ - 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -(4- o-'. hydroxyphenyl)pyrazol-3 -yl]ureau\ U / oTH H X cor 'X XX'"0H 1 -[(45)-chroman-4-yl]-3-[ 1 -(3 - a.,. / methylsulfonylphenyl)pyrazol-3-yl]urea O'"'A o -X'XA X AX \N' 'N" N t r (jr hl H1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - \ PH(1 -hydroxy- 1 -methyl- o"' X o X- ethy l)pheny 1 ] py razol -3 -y 1 ]urea X A J,. Jl k >- / ■I, xr N- " N V, / I? F H H —1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 - cr"' X o..-" N (5,6-dimethoxy-3-pyridyl) pyrazol-3- J... A A,.N-A W yl]urea IT 'N' N \~s / 'H H0 —Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[3 - F fluoro-4-(methylamino) phenyl]pyrazol- )3-yl]urea G,A " N: NH. jHf1 -[(45)-chroman-4-yl]-3-[ 1 -[4- 0 r % / =\ 9 / (methylsulfamoyl)phenyl]pyrazol-3- zS, J.. A.,yl]u e N N A / j* r a j H Hc1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[6- (methylamino)-3-pyridyl] pyrazol-3- Cl^ KNH yl]urea f V N ■■ 1JH11 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- O'-'A < A" A PH [2,2,2-trifluoro- 1 -hydroxyG....." " H X- / A ethyl ]pheny 1 ] py razol -3 -y 1 ]urea (C4) " V AJ H f A-f F p 1 -[(45)-8-chlorochroman-4-yl]-3 -[ 1 -[4- J’"”'" \; A pH [2,2,2-trifluoro- 1 -hydroxyG.....ethyl ]pheny 1 ] py razol -3 -y 1 ]urea (C4) AJ H f A--F A p 6-[3-[[(45)-8-chlorochroman-4- cXX 0 ■-A \ HN'-- y 1 ] carb amoy 1 amino] py razol - 1 -y 1 ]-7V- ci-,x1 1 J- ''Nmethy 1 -py ri dine-3 -carb oxami dei Hl-[(45)-8-chlorochroman-4-yl]-3-[5- () / ■ A.. m ethyl- 1 -(3 -methyl sulfonyl O ' 0... _ / 0 phenyl)pyrazol-3-yl]urea Ch... A. N- - X A. N' A XN ' Nl-[(45)-8-chlorochroman-4-yl]-3-[4- OxVi / m ethyl- 1 -(3 -methyl sulfonyl phenyl) O '" X £' ■' znpyrazol-3-yl]urea a.... A X 1; N-..< A•" " V AXHl-(8-cyanochroman-4-yl)-3-(l-phenyl- ONGl / Z-pyrazol-3 -yl)ureaA1. N" N Ay k JHHAttorney Docket No. PTZ-011WOTable 1XChemical Name Structure O. - z l-(8-cyanochroman-4-yl)-3-(l-phenyl- rl / / -pyrazol-3 -yl)urea J. I, L N-X b r' N N ' A A" " Nj H H f i(5)-5-(3-(3-(8-chlorochroman-4- o'— V, f''° _ £ "yl)ureido)- 1 / / -pyrazol - 1 -yl) n«-zA. • picolin d -K' ZIami e Y -N v / NH2ZI(5)- 1 -( 1 -(4-(2-aminopropan-2- O'''"''yl)phenyl)- lJ7-pyrazol-3 -y l)-3 -(8-chloro- Ck, X h } lAAVN’ 6-fluorochroman-4-yl)urea O / A b 'W '" NT 'N 'V. \H HxIJF(5)-4-(3-(3-(8-methylchroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl) benzamide IZ IZ> >°°= IZ IZ(5)- 1 -( 1 -(2-(dimethylamino)ethyl) - \H- ck— | oHpyrazol-3-yl)-3-(8-methyl chroman-4- / f °yl)urea H H \f A WW / o(5)-2-(3-(3-(8-chlorochroman-4- 0yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- methylbenzenesulfonamide JI(5)-4-(3-(3-(8-chlorochroman-4- F yl)ureido)- 1 / / -pyrazol - 1 -yl)-2- NH2CL 1 1 A k f _ / fluorobenzamide A— A '"'N'— N-^N v h l H H - 0 (5)-4-(3 -(3 -(8-fluorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl) benzamide(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- CL 1 J. II N \ / ? hydroxyethyl)benzamide ( J H H —7HVAQHAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure4-(3-(3-((5)-8-chlorochroman-4- o; Xyl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 -Cl\ / L J- I 1 N_ / ^\ 0 hydroxypropan-2-yl)benzamideMHHW-OH 4-(3-(3-((5)-8-chlorochroman-4- oyl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 - CL 1 J, J [ N_ / ^\ 0 hydroxypropan-2-yl)benzamide-OH (5)-4-(3-(3-(8-chlorochroman-4- Oyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- CL 1 J. II X7 N— / \ zP (dimethylamino)ethyl)benzamide (I^J H H\ (5)-4-(3-(3-(8-chlorochroman-4- TZyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- >° / \ r— I4H amino)ethyl)benzamide | J H H TZ(methyl HN— - / (5)-4-(3-(3-(8-chlorochroman-4- ^3o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- CL 1 J.. A \ V— / (cyclopropylmethyl)benzamide H H —A4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 -CIV Y ^"’’NZ^N / ^NZ\ / hydroxypropan-2-yl)benzamide T J H H -7HN^y OH4-(3-(3-((5)-8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 - ci 1 J II L N- — v V / / hydroxypropan-2-yl)benzamide r J H H HN-V 9_QH (5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 - CL 1 J. II 9 (hydroxymethyl)cyclopropyl) benzamide Yf \ / - \ / KH H' / HN-_L> OH(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(5- (m ethyl sulfonyl)pyri din-3 -yl)- 1H- pyrazol-3-yl)ureaAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure (5)-6-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)nicotinamide(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(4- m ethoxy-3 -(methyl sulfonyl) phenyl)- l / 7-pyrazol-3-yl)urea(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(3 - o o o ofluoro-5-(methylsulfonyl) phenyl)- \H- pyrazol-3-yl)urea(5)-5-(3-(3-(8-chlorochroman-4- IZ IZ IZ IZ 0 «==\ / =N NH yl)ureido)- 1 / 7-pyrazol - 1 -yl) pyrimidine- 2-carboxamide H I h° IZ IZ IZ IZH HN0 (5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- h) 0 (m ethyl sulfonyl)ethyl)- l / 7-pyrazol-3 - 0yl)urea6H HAA ( (5)-5-(3-(3-(8-chlorochroman-4- I ro yl)ureido)- 1 / 7-pyrazol - 1 -yl) pyrazine-2- carb oxami de? fkA|| 1 H HN0NH2(5)- 1 -(8-fluorochroman-4-yl)-3 -( 1 -(4-0<^° m ethoxy-3 -(methyl sulfonyl) phenyl)- l / 7-pyrazol-3-yl)urea F 1 \ II / — \ y— c / 11 1H H(5)- 1 -(8-chlorochroman-4-yl)-3 -(1- cyclopropyl-l / Z-pyrazol-3-yl) urea(5)- 1 -( 1 -( 1 -acetylpiperidin-4-yl)- 1H- pyrazol-3-yl)-3-(8-chloro-chroman-4- yl)ureaAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - isopropylpiperidin-4-yl)-lJ7-pyrazol-3- yl)urea(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - ethylpiperidin-4-yl)-lJ7-pyrazol-3- yl)urea II J H H(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-N, N- dimethylacetamide c O o. ID|| 1 H H2-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-N, N- dimethylpropanamide IZ IZIZ IZ2-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-N, N- dimethylpropanamideA A\^oo,1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - 00, - / methyl-2-oxopiperidin-4-yl)-lJ7-pyrazol- 3-yl)urea \-~_y ~~II 1H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - cyclopropylpiperidin-4-yl)-lJ7-pyrazol- 3-yl)ureaCIV0>NANXN'O-<|| \ H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - methylpyrrolidin-3-yl)-lJ7-pyrazol-3- yl)ureaI JH H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - methylpyrrolidin-3-yl)-lJ7-pyrazol-3- yl)urea || \ H HAttorney Docket No. PTZ-011WOTable 1 CM CM I 1 T Chemical Name Structure 1 1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - methyl-5-oxopyrrolidin-3-yl)-l / 7- o O ° ° pyrazol-3-yl)urea || J| H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1 - Q Qmethyl-5-oxopyrrolidin-3-yl)-l / 7- ci JO A ZI ZIpyrazol-3-yl)urea 4 °zr ZT(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(4- (methylsulfonyl)pyridin-2-yl)-l / 7- C—pyrazol-3-yl)urea oo O(. S’)- 1 -( 1 -(4-(2-aminopropan-2-yl)-3 - (methyl sulfonyl)phenyl)- 1 / 7-py razol -3 - IZyl)-3-(8-chlorochroman -4-yl)ureab°IZ(5)- 1 -( 1 -(4-( 1 -aminocy cl opropyl)-3 - 0 (methyl sulfonyl)phenyl)- 1 / 7-py razol -3 - 0=^— yl)-3-(8-chlorochroman -4-yl)urea|| 1 H H — NH2(. S’)- 1 -( 1 -(4-(3 -aminooxetan-3 -y 1 ) -3 - 0 (methyl sulfonyl)phenyl)- 1 / 7-py razol -3 - 0=^— yl)-3-(8-chlorochroman -4-yl)ureacyA0rA / A r°[1 i H H — NH2(5)-l-(l-(6-amino-5-(methyl- sulfonyl)pyri din-3 -yl)- 1 / 7-py razol -3 -y 1)- 3-(8-chlorochroman -4-yl)urea(5)- 1 -(8-fluorochroman-4-yl)-3 -( 1 -(4- 0 m ethoxy-3 -(methyl sulfonyl) phenyl)- 0=^— l / 7-pyrazol-3-yl)ureaF 1 J 11 L. / — \ _ r / || \ H HAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure 2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V,7V,4- o^V o V / trimethylpentanamide CI 1 J 1 X \|| 1 H H _ _ / 2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V,7V,4- (V o V / trimethylpentanamide CI 1 J I V \[I J H H _ / O2-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)-l / / -pyrazol-l-yl)-3-hydroxy-0v\A, A-dimethylpropanamideQ\>H HHO IZ2-(3-(3-((5)-8-chlorochroman-4- yl)ureido)-l / / -pyrazol-l-yl)-3-hydroxy- IZA, A-dimethylpropanamideVI \(5)-2-(3-(3-(8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- ci V i rV ^ methylacetamide|| 1 H H(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- cyclopropylacetamide n ° nX|| 1 H H(5)- 1 -( 1 -(2-(azetidin- 1 -yl)-2-oxoethyl)- 0 U / -pyrazol-3-yl)-3-(8-chlorochroman-4- ycy'V ° rV^ / ^~N\ / l)urea>|| J H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- O morpholino-2-oxoethyl)-lJ7-pyrazol-3- o'" V o Vi / / yl)urea CL V V V \ — H I H H / Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure (5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl )-A -methyl - c, D i A AA-(pyridin-2-ylmethyl) acetamide|| 1 H H N—_ A (5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- 0, _, oxo-2-(piperidin-l-yl)ethyl)-lJ7-pyrazol- 3-yl)ureaCln ^ xA~^|| J H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- 0 oxo- 1,2-dihydropyri din-3 -yl)- 1H- o O 0 V— NH pyrazol-3-yl)ureaCl[1 1H H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - methyl-2-oxo-l,2-dihydropyri din-3 -yl)- IZ IZl / / -pyrazol-3-yl)urea h°IZ IZ(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2-(4- methylpiperazin- 1 -yl)-2-oxoethyl)- 1H- pyrazol-3-yl)ureaClID X xA O - 1 j|h h(5)-4-(3-(3-(8-chlorochroman-4- 0^1 o Z~A ° yl)ureido)- 1 / / -pyrazol - 1 -yl) ci 1 J 11 JL, — \ V / / cyclohexane- 1 -carboxamide [I \ H H NH2(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl) piperidine- 1 -carboxamideCIV||Q J >NHANHXN~O — -< NH2(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1, 1 - dioxidotetrahydro-2H-thiopyran-4-yl)-Cii j ji r\ _ / * l / / -pyrazol-3-yl)urea || J H H — ° 1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1, 1 - di oxidotetrahydrothi ophen -3 -yl)- 1H- pyrazol-3-yl)ureaAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure 1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(1, 1 - di oxidotetrahydrothi ophen -3 -yl)- \H- pyrazol-3-yl)urea(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(4- O'''"'""'] 0.(dimethylamino)cyclohexyl) -1H- pyrazol-3-yl)urea || J H H \ (5)-7V-(4-(3-(3-(8-chlorochroman-4- O yl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl)- CL x A x? \ N N-m ethyl acetami de o O o || J H H \ (5)-7V-(4-(3-(3-(8-chlorochroman-4- 00"' ^, 0 _ yl)ureido)- 1 / / -pyrazol - 1 - yl)cyclohexyl)acetamideli ihIZ IZ IZhb°(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- IZIZ IZmethoxypyridin-4-yl)-l / / -pyrazol-3- CL 1 1 JI / N^Z V yl)urea|| 1 H H(5)-7V-(2-(3-(3-(8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)ethyl)-7V- methylacetamide o1 || H H1 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1H- pyrazol-3-yl)-3-((5)-8-chlorochroman-4- yl)urea1 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1H- pyrazol-3-yl)-3-((5)-8-chlorochroman-4- yl)ureaAttorney Docket No. PTZ-011WOTable 1Chemical Name StructureyrJ ' • 7V-(3-(3-(3-((5)-8-chlorochroman-4- 0, yl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl)"" N^N^N \ _ / acetamideH H \ / Q Q ZI7V-(3-(3-(3-((5)-8-chlorochroman-4- ZI4 °yl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl) 4 zz °ZIacetamideo o o o7V-(3-(3-(3-((5)-8-chlorochroman-4- oyl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl) oacetamideIZ IZ IZ IZ7V-(3-(3-(3-((5)-8-chlorochroman-4- IZyl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl) IZ IZ IZacetamide(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(4- (methylamino)cyclohexyl)-l / / -pyrazol- 03-yl)urea° 1 (5)-7V-(2-(azetidin- 1 -yl)ethyl)-4-(3 -(3 -(8 -Zchlorochroman-4-yl)ureido)-l / / -pyrazol- 1-yl) benzamide4-(3-(3-((5)-8-chlorochroman-4-? rAi / ^\ / °nyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(l -cyano- 2-methylpropyl) benzamide fl J H H - ' HN—4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(l - cyanopropyl)benzamideAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 - c'XXxXzO y / cyanopropyl)benzamide M H H — ' HN— 4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 - cyanopropyl)benzamide 1 J H H — ' HN— / (5)-4-(3-(3-(8-chlorochroman-4- 00yl)ureido)- 1 / / -pyrazol - 1 -y l)-zV-(( 1 - Q| I I II JL N- — / y / / methoxycyclopropyl)methyl) benzamide V / \ \H H(5)-4-(3-(3-(8-chlorochroman-4- o^X o ^yoyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- Qi 1 I II JL N- — < y / / (ethyl(methyl)amino)ethyl) benzamide H H -4-(3-(3-((5)-8-chlorochroman-4- y" X o ^yoyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- Q| 1 J 11 JL, — A V / / methoxypropyl)benzamideVxJH H— HN—(5)-4-(3-(3-(8-chlorochroman-4- o^X? / ° yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-((3 - methyloxetan-3-yl)m ethyl) benzamideH H—4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- ci \y 1%y J ■'"»N'XI^N-XX^. N \ / / y / \ fluorocy cl opropy 1) m ethy l)b enzami de 1 T H H — ' Hby £>—F4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- ci \y 1%y J ■'"»N'Xl^N-Xx^. N \ / / \ fluorocy cl opropy 1) m ethy l)b enzami de 1 T H H — ' Hby £>—F4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- ci \y i%y J ■'"»N'Xl^N-Xx^. N / M \ / / \ fluorocy cl opropy 1) m ethy l)b enzami de 1 T H H — ' Hby £>—FAttorney Docket No. PTZ-011WOTable 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 fl T H H — / HN^£>— F (5)-7V-(bicyclo[ 1.1.1 ]pentan- 1 -yl)-4-(3 - (3-(8-chlorochroman-4-yl)ureido)-U / - pyrazol-l-yl) benzamideI JH H- Nz? 4-(3-(3-((5)-8-chlorochroman-4- o / ==\ o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- o(dimethylamino)propyl) benzamide l| 1 H H HN — v * / o H 4-(3-(3-((5)-8-chlorochroman-4- IZ o / ^\ ° yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- (dimethylamino)propyl) benzamide IZo M 4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((l - O ii A-AH ° methylazeti din-2 -yl)methyl) benzamide fl J H H - / HN—4-(3-(3-((5)-8-chlorochroman-4- oyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(l - cyanopropan-2-yl)benzamide fl fl H H r HN^Z\ — = 2N 4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(l - cyanopropan-2-yl)benzamide fl fl H H — HN^ / \ — =N (5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((l - cyanocyclopropyl)methyl) benzamide fll JJ H H - HN^— =N4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2- cyanocyclopropyl)methyl) benzamideAttorney Docket No. PTZ-011WOTable 1Chemical Name Structure4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((2,2- fs i o ° difluorocyclopropyl)methyl) benzamide 1 H H — / HN^LXF(5)-A-((l -aminocyclopropyl) methyl)-4- (3-(3-(8-chlorochroman -4-yl)ureido)-CIVVAAN'1 / / -pyrazol - 1 -yl)benzamide |^JH HH CN^^NH2A-((2-aminocyclopropyl)methyl)-4-(3- (3-((5)-8-chlorochroman-4-yl)ureido)- 1 / / -pyrazol - 1 -yl)benzamide [I JHH - HN^(5)-4-(3-(3-(8-chlorochroman-4- 0^ 0 7=^ 0 yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-((3 - pi 1 J J] L N- — \ ZV / \ N cyanooxetan-3-yl)methyl) benzamide H H - HN—(S)-N-((3 -aminooxetan-3 -yl)methyl)-4- (3-(3-(8-chlorochroman-4-yl)ureido)- 1 / / -pyrazol - 1 -yl)benzamideH H^2(5)- 1 -( 1 -benzyl- l / / -pyrazol-3 -yl)-3 -(8- omethylchroman-4-yl)ureaL JH H(5)- 1 -(6-fluorochroman-4-yl)-3 -( 1 - O / ===phenyl- l / / -pyrazol-3-yl)urea|l 1H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - ohy droxy cyclopen tyl)-l / / -py razol -3-ck J- / ZA / \ *]yl)urea || J H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - hy droxy cyclopen tyl)-l / / -py razol -3-ci\ 'Y: / "' / Z / XA / *1'''Y N N N V Jyl)urea [1 J H H \OHAttorney Docket No. PTZ-011WO Table 1Chemical Name Structure1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - CA'\| Ohy droxy cyclopen tyl)-l / / -py razol -3- Cl J. 1, / CN / \ *1 yl)urea || J H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - hy droxy cyclopen tyl)-l / / -py razol -3-ck A J- A AA \ *] yl)urea || J H H (DH1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - hy droxy cyclopen tyl)-l / / -py razol -3- Cl J. 1. AYK \ *1|| J H H \)H yl)urea1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -(3 - hydroxy cyclobutyl)- l / / -pyrazol-3 - CL A A A., / A-OH yl)urea H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 -((15, O^Z 03R)-3 -hydroxy cyclobutyl)- l / / -pyrazol-3- Ck J- JL \ 2 — OH yl)urea H H(5)-4-(3-(3-(8-chlorochroman-4- O^^I 0Ck A J. 0 / z0Hyl)ureido)- 1 / / -pyrazol - 1 -yl)benzoic acid4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -y 1 )- N-(((R)- 1 - °'^xi o H CL 1 J J 1NH methylazeti din-2 -yl)methyl)benzamide. K4-(3-(3-((5)-8-chlorochroman-4- o H \Nyl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(((5)- 1 - ck A J X / N\ methylazeti din-2 -yl)methyl)benzamide. a. TANX. A-'k (5)-5-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-((3 - N N N \\ / / \ methyloxetan-3-yl)methyl)picolinamide H H — N HN—Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure (5)-4-(3-(3-(8-chlorochroman-4- Y ° Y\ / — \0yl)ureido)- 1 / / -pyrazol - 1 -yl)-N, N- dimethylpiperidine- 1 -carboxamideCLN H N H N - (5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - OZ 0\ o (ethylsulfonyl)piperidin-4-yl)-lJ7- Ck J. 1 N— H pyrazol-3-yl)urea yy YY A / Y(5)-4-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- methylpiperidine- 1 -carboxamide H \ H H - / NH 1 -( 1 -( 1 -acetylpyrrolidin-3 -yl)- 1H- pyrazol-3-yl)-3-((5)-8-chlorochroman-4- ciyl)urea YO- AYJ 'N YYN1 -( 1 -( 1 -acetylpyrrolidin-3 -yl)- 1H- pyrazol-3-yl)-3-((5)-8-chlorochroman-4- yl)urea CI YO.. A XXY YY " ^-^01 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1H- °' / ~Y 0 - pyrazol-3-yl)-3-((5)-chroman-4-yl)ureaAZH H1 -( 1 -( 1 -acetylpiperi din-3 -yl)- 1H- cYY o r^\, —. pyrazol-3-yl)-3-((5)-chroman-4-yl)urea / Y / J -hY A^i\r Y Yl Y \ _ YH H(5)- 1 -(chroman-4-yl)-3 -(1 -(2-(pyridin-4- yl)ethyl)-lJ7-pyrazol-3-yl)ureaGOI VAQAttorney Docket No. PTZ-011WOTTable 1 o Chemical Name Structure (5)-2-(3-(3-(8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V- O^U O rz=\ V-NH ethyl acetamide Cl JI 1.H H(5)-2-(3-(3-(8-chlorochroman-4- o yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-ethyl-7V- O"" U \ °^ O rcAA methylacetamide ci i.H H1 -((5)-8-chlorochroman-4-yl)-3 -( 1 - O^U O r==\ / -. ((lA,45)-4-(dimethylamino)cyclohexyl)- C ol JI 1 \. l / l / / -pyrazol-3-yl)urea H \ H H - ' \(5)-2-(3-(3-(8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- hydroxyethyl)acetamide(5)-2-(3-(3-(8-chlorochroman-4- OH yl)ureido)- 1 / / -pyrazol - 1 -yl)-7V-(2- hydroxyethyl)- / ' / -rn ethyl acetamideci JU;if JH H(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(2- Cl(pyridin-4-yl)ethyl)-lJ7-pyrazol-3- yl)ureaooHN NNT XJAJJl-((5)-8-chlorochroman-4-yl)-3-(l-(4- O-^U O - - (methylamino)cyclohexyl)-lJ7-pyrazol- 3-yl)ureaciUJ. U v vU[1 JH HAttorney Docket No. PTZ-011WO Table 1Chemical Name Structure7V-(4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -yl)cyclohexyl)- A-m ethyl acetami de X ^H A HJCA -A-1 \ (5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -(1 - (methylsulfonyl)piperidin-4-yl)-lJ7- Gk X / Xx, / \ N— pyrazol-3-yl)urea J H H 8 methyl (5)-4-(3-(3-(8-chlorochroman-4- °X0A\ / - \ 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)piperidine- 1 - carboxylatec|\ x. y- H x. H / X, / ( - 0 _ (5)-2-(3-(3-(8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 -yl)acetic acid o^A0A\ A~0Hc< X J- X XK, / H H4-(3-(3-((5)-8-chlorochroman-4- yl)ureido)- 1 / / -pyrazol - 1 -y l)-7V-( 1 -C? X0r^\'\X. J- A X / ^XX / / ° N cyanopropyl)benzamide XI H H X 7V-(4-(3-(3-((5)-8-chlorochroman-4- 0 yl)ureido)- 1 / / -pyrazol - 1 - yl)cyclohexyl)acetamidecix PA A H N HAX -7!^ 1 -(8-fluorochroman-4-yl)-3 -( 1 -(4- methoxy-3 -(methyl sulfonyl)phenyl)- 1H- v° pyrazol-3-yl)ureaFIX ' N X AM / H H- 1 -( 1 -(4-(2-aminopropan-2-yl)phenyl)- H HNH2 U / -pyrazol-3-yl)-3-(8-chloro-6- CL 1 1 A A.. / \\ / ) — A fluorochroman-4-yl)urea H \ H H - \Attorney Docket No. PTZ-011WOTable 1Chemical Name Structure1 -( 1 -(4-(2-aminopropan-2-yl)phenyl)- ° / =\U / -pyrazol-3-yl)-3-(chroman-4-yl)ureaA II A 1 N H-A-N HA'HJHx""’1 -((47?)-8-chl oro-2 - (methoxymethyl)chroman-4-yl)-3-(l- phenyl-l / 7-pyrazol-3-yl)ureao A 0 _CI^AA A1 -((47?)-8-chl oro-2 - (methoxymethyl)chroman-4-yl)-3-(l- phenyl-l / 7-pyrazol-3-yl)ureaA O _ci^AA A1 -((47?)-8-chl oro-2 - OH(hy droxymethyl)chroman-4-yl)-3 -( 1 - phenyl- l / 7-pyrazol-3-yl)urea ° / A O r=\ci^ vA A A A Az AJ A HANH^N AA / 1 -(8-cyanochroman-4-yl)-3 -(1 -phenyl- l / 7-pyrazol-3-yl)ureaN& i -1 ii LH H—(5)- 1 -(8-chlorochroman-4-yl)-3 -( 1 -Dx D (phenyl -t / s )- 1 / 7-py razol -3 -yljurea0XvCW A A' T>0 H J H H AA

[0087] 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):Attorney Docket No. PTZ-011WOFormula (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;R7 is H, methyl, CHCH3CH2OH, CH2COHCH3CH3, CH2CHCH3OH, or CH2CH2ORe; andn is 1-4; and *denotes a chiral carbon.Attorney Docket No. PTZ-011WO

[0088] In some embodiments, a compound of formula (II) is a compound listed in Table 2.Table 2Chemical Name Structure(IS)- 1 -(8-chlorochroman-4-yl)-3 - H (IZ / pyrrolof oA o rYA"N\ 3,2-Z>]pyridin-5-yl)urea Ck A J A Jl Ay j H H(IS)- 1 -(8-chlorochroman-4-yl)-3 -(6- methylpyridin-2-yl)urea 0n «¥ ¥ / \TXN "xUH(IS)- 1 -(8-chlorochroman-4-yl)-3 - 0'^'1 o(pyridin-2- yl)urea Cl M kf Ti A N N N [I I H H(! S)-6-(3-(8-chlorochroman-4- yl)ureido)-N-methylpicolinamide(Cl 5) Cl\kkA / N Ti N N N rf - H J H H II(! S)-6-(3-(8-chlorochroman-4- o" N o / "■A yl)ureido)picolinamideCk A J-, A Jk r N N V YNH2MH H0(! S)-6-(3-(8-chlorochroman-4- 0 r p 1 yl)ureido)-N, N-dimethylpicolinamideCIYY -A.bL A. - |l^ H HN¥x0(! S)-l-(8-chlorochroman-4-yl)-3-(5- (hydroxymethyl)pyridin-2-yl)ureaci^ A X. A A JNN N|l 1 H HAttorney Docket No. PTZ-011WOTable 2Chemical Name Structure 6S)-l-(5-acetylpyridin-2-yl)-3-(8- chlorochroman-4-yl)urea(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- ethoxypyridin-2-yl)urea(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- cyanopyridin-2-yl)ureaf$-l-(6-(lH-imidazol-2-yl)pyridin-2- yl)-3-(8- chlorochroman-4-yl)ureaf59-6-(3-(8-chlorochroman-4- yl)ureido)- 3 -methylpicolinatefiS9-6-(3-(8-chlorochroman-4- yl)ureido)-3- methylpicolinic acidfiS9-6-(3-(8-chlorochroman-4- yl)ureido)-N, N,3- trimethylpicolinamidefiS9-l-(8-chlorochroman-4-yl)-3-(6- cyclopropoxypyridin-2-yl)ureaAttorney Docket No. PTZ-011WOTable 2Chemical Name Structure(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- 0 0(pyrrolidin- Cl A 1,1 -yl)pyri din-2 -yl)urea ■ ■ N N1J H H 1 / l-(fiS9-8-chlorochroman-4-yl)-3-(6-(2- oX o rT hydroxypropyl)pyridin-2-yl)ureaA A XX 'N NH I H HorCIXA J-., A Ao H J " N'^X^*'OH H HfiS9-2-(6-(3-(8-chlorochroman-4- o' X o tr A o yl)ureido)pyridin-2-yl)acetamide CK / k AJ)-.,. A J. N A A NH2I J « IZ Hethyl f59-2-((6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)oxy)acetate oX o Ack X / LA A A|l JI N N NA O T H H i 1 flS9-2-((6-(3-(8-chlorochroman-4- O" "yl)ureido)pyridin-2-yl)oxy)acetamide °ci. A (f, 0 N o r u H 1 3 NH2(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- cyclopropylpyridin-2-yl)urea I NX(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- O '(hydroxymethyl)pyridin-2-yl)urea Ck., L X 'N" NH HIXAttorney Docket No. PTZ-011WOTable 2Chemical Name Structure(S)- 1 -(chroman-4-yl)-3 -(6- O(hydroxymethyl)pyridin-2-yl)urea "i -4 Jx.. OH■: 'N ■ ' Nc JHH(S)- 1 -(6-acetylpyri din-2 -yl)-3 -(8- O" X 0chlorochroman-4-yl)ureaA N N|l J H Hl-(fiS9-8-chlorochroman-4-yl)-3-(6-(l- hydroxyethyl)pyridin-2-yl)ureao / II _ d H H |o ■ or \ V y\ / o^X o XXZES H I H H | fiS9-6-(3-(8-chlorochroman-4- ryl)ureido)-N-(2- 1, N...-'X hydroxyethyl)-N-methylpicolinamide N' -fv-' OH H5fiS9-6-(3-(8-chlorochroman-4- 4 oyl)ureido)-N-(2- rck.. X, I 1 Ji H (dimethylamino)ethyl)picolinamide N NH H01fiS9-6-(3-(8-chlorochroman-4- o" X oyl)ureido)-N-(2- Ck X,d (rkx0Hhydroxyethyl)picolinamide NH I JH>(AJ-N-(2-amino-2-oxoethyl)-6-(3-(8- 0'^ 1010chlorochroman-4-yl)ureido)-N- Ck A. / L Jmethylpicol 'N' iinamide " N- NH2H H XJfiS9-6-(3-(8-chlorochroman-4- 0" | OH yl)ureido)-N-(2- ci. A. il L" 'N N " x, N.., J<' hydroxy-2-methylpropyl)-N- H Hmethylpicolinamideu 0Attorney Docket No. PTZ-011WO o / Table 2Chemical Name Structuref59-6-(3-(8-chlorochroman-4- O'^Xi 0yl)ureido)-N-(2- A°Ck A A x n;, (dimethylamino)ethyl)-N- N yN" o methylpicolinamide 6 J f59-6-(3-(8-chlorochroman-4- yl)ureido)-N-(2- cyanoethyl)-N-methylpicolinamide CK AJAO N Y CN 0 H H 0f59-6-(3-(8-chlorochroman-4- yl)ureido)-N-(2- li N N N N tf O methoxyethyl)picolinamide 0 H H if | 6-(3-(f59-8-chlorochroman-4- yl)ureido)-N-((AJ- l-hydroxypropan-2-yl)picolinamide Y ' N NH I H H6-(3-(f59-8-chlorochroman-4- 0^ 0 r T 1Zyl)ureido)-N-((AJ- ck A J- A A 2-hydroxypropyl)picolinamide X [iI Y J N NH H AY / / X ' _L 16-(3-(f59-8-chlorochroman-4- 1 CT0 0 ryl)ureido)-N -((R) - 1V N -iAHN Y x-v l-hydroxypropan-2-yl)picolinamide Y A N N y|| J H H o OH 0 * 6-(3-(f59-8-chlorochroman-4- cA'l 0 [1‘yl)ureido)-N -((R) - ^1HI Ck,-L J,(A JY '■A'- 'N N' 2-hydroxypropyl)picolinamide N YNV'ZX0H = H H0(AJ-N-(3 -amino-3 -oxopropyl)-6-(3 -(8- 0chlorochroman-4-yl)ureido)-N- ci- A J Av x, NH2A A' ''N N methylpicolinamideNA f 0 0 LAH H(S)- 1 -(chroman-4-yl)-3 -( 1 H- pyrrolo[3,2- CA0 cb]pyridin-5-yl)urea AJ- J 'N[I J HAttorney Docket No. PTZ-011WO Table 2Chemical Name Structurel-(6S)-8-chlorochrornan-4-yl)-3-(5-(l- hydroxyethyl)pyridin-2-yl)urea5J-8-chlorochroman-4-yl)-3-(6-(2,2,2- trifluoro-1 -hydroxy ethyl)pyridin-2- yl)urea 'p iT N N N 1 F O UH HAHo F A A Ak F f N N N T F UH HOH(S)- 1 -(8-chlorochroman-4-yl)-3 -(6- ((methylsulfonyl)methyl)pyridin-2- O'A ^ Oo=xz0. yl)ureaXj H NNb 1 -(6-{(R)- 1 -acetylpiperi din-3 - yl)pyridin-2-yl)-3-z>— (8-chlorochroman-4-yl)urea o T x 1 H H ^lo r7|<;r N N N T 1 H J nHI I0"^Attorney Docket No. PTZ-011WOTable 2Chemical Name Structure6-(3 -(7 -cy anochroman-4-yl)ureido)-N - methylpicolinamide (A oA J- A, 1 J H \ AJI J N / - H H0 A(AJ-6-(3-(7-cyanochroman-4- yl)ureido)-N-methylpicolinamide oA 0X [j J A J. " N 1 N", H -A A -bk N - 1 / JH H0 rA(R) -6-(3 -(7-cy anochroman-4- yl)ureido)-N-methylpicolinamide o'A oA X A J jHA JH H0f59-6-(3-(7-chlorochroman-4- yl)ureido)-N-methylpicolinamide oA O r H C 1V J.„ A JN^N'crHNX JUHo (7? J-6-(3-(7-chlorochroman-4- yl)ureido)-7V-methylpicolinamidej A I A N m X YN- cr^ ° l-(f59-8-chlorochroman-4-yl)-3-(6- W-3- hydroxypyrrolidin-l-yl)pyridin-2- Ck D - A XX. yl)urea J J HHL 7OHAttorney Docket No. PTZ-011WOTable 2Chemical Name Structurel-(f59-8-chlorochroman-4-yl)-3-(6- (.(S)-3- O^Y 0 rYY hydroxypyrrolidin-l-yl)pyridin-2- n 1 J jj J J yl)urea I V " N N 'N'- - N YH HO OH(S)- 1 -(6-(4-(2-aminopropan-2- yl)phenyl)pyridin-2-yl)-3 -(8 - O'Y 0 YY chlorochroman-4-yl)ureaV ” ” O • " Ya 1 - (6 - ( (S) - 1 -aminoethyl)pyridin-2-yl)-3 - (-8- O^Y0YA chlorochroman-4-yl)ureaCI\ 7AI YJp A NA NA NA t^NH2 || 1 H H |or OY0YATI Y N N N J|l J H H |N-((7? J- 1 -(6-(3 -(8-chlorochroman-4- O '" ""1 0 [f Li yl)ureido)pyridin-2-yl)ethyl)acetamide CK A, XTi Y N N 'N' Y Y [1 J H H | II OfCl. tl A JO N, ■'(J If 1 'N- y Y (S)- 1 -(8-chlorochroman-4-yl)-3 -(6-(2- methyl- O'"""'-] 02H- 1,2,3 -tri azol-4-yl)pyri din-2 -yl)urea1 H H v I.NN- -■" NAttorney Docket No. PTZ-011WOTable 2Chemical Name Structuref59-l-(8-chlorochroman-4-yl)-3-(6-(3- O'”hy droxyoxetan-3-yl)pyri din-2 -yl)urea OH ci... AJ H H t I A(S)- 1 -(8-chlorochroman-4-yl)-3 -(6-( 1 - hydroxy cyclopropyl)pyridin-2-yl)ureac )H ° A.f N ' hr 'N / zJ n riOl-(fiS9-8-chlorochroman-4-yl)-3-(5- fluoro-6-(l- (Ahydroxyethyl)pyridin-2-yl)urea ■1W 1 ] 1 ] X - n norC<1. A 1 X,o H - N N N XH H | fiS9-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)-N, N- o"v) dimethylacetamide X NXH H 1fiS9-2-(6-(3-(8-chlorochroman-4- yl)ureido)pyridin-2-yl)-7V- ) methylacetamide ok A.r IJAttorney Docket No. PTZ-011WOTable 2Chemical Name Structure 6S)-6-(3-(8-chloro-6-methoxychrornan- 4- yl)ureido)-A-methylpicolinamidel-(f59-8-chlorochroman-4-yl)-3-(6-(l- methoxyethyl)pyridin-2-yl)ureaf59-6-(3-(8-chlorochroman-4-... F yl)ureido)-3- 2 n H fluoro-A-methylpicolinamideH H AN-( (S)~ 1 -(6-(3 -(-8-chlorochroman-4- yl)ureido)pyridin-2- yl)ethyl)methanesulfonamidef59-6-(3-(8-chlorochroman-4- yl)ureido)-7V,7Vdimethylpyrazine- 2-carboxamide(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- methyl- / / / pyrrolo[2,3-b]pyridin-6-yl)ureaAttorney Docket No. PTZ-011WOTable 2Chemical Name Structure(S)- 1 -(6-(4-(3 -aminooxetan-3 - yl)phenyl)pyridin-2-yl)-3-(8- chlorochroman-4-yl)urea CK JL, 1? c''hT " N'' INhi H U V‘" O(S)- 1 -(2-acetylpyrimidin-4-yl)-3 -(8- / \ w> / _ \ / chlorochroman-4-yl)urea ox0o C ~ ol _, X.oH H0 l-(f59-8-chlorochroman-4-yl)-3-(2-(l- / ' X y A / / \......hydroxyethyl)pyrimidin-4-yl)urea X OA N N X NX / Y H H OHl-(f59-8-chlorochroman-4-yl)-3-(2-(l-:N hydroxyethyl)pyrimidin-4-yl)urea' -1 A -N' J LH H N A Y OH or 0y. x. 1 A / N LJ" N -N' Y j rl E rllOHf59-l-(8-chlorochroman-4-yl)-3-(2- H methy 1 - / / / -pyrrol o [ O'" > 0 t3,2-b]pyridin-5-yl)urea-- J- ''NA bf 1 -N'- H HAttorney Docket No. PTZ-011WOTable 2Chemical Name Structurel-((S)-8-chlorochroman-4-yl)-3-(2- (2,2,2- tri fluoro- 1 -hydroxy ethyl)pyrimidin-4- CK. X J A X < X CcFyljurea T| N N N T F MH HOH(IS)- 1 -(8-chlorochroman-4-yl)-3 -(2-(2- methyl- 2H- 1,2,3 -triazol-4-yl)pyrimidin-4- Ch 1 X 1 1 J- yljurea "-[j- A A f N- JH H':?;N (IS)- 1 -(8-chlorochroman-4-yl)-3 -(6-(2- methyl- o -i o2H- 1,2,3 -triazol-4-yl)pyrazin-2-yl)urea CR X X A X J- - N 11 T N N N|l _., | H H V N—(IS)- 1 -(8-chlorochroman-4-yl)-3 -(4-(2- methyl- O'xi 0 >i2H- 1,2,3 -triazol-4-yl)pyrimidin-2- yljurea Ck A X. A A J)A " V N N N VX JH H(IS)- 1 -(8-chlorochroman-4-yl)-3 -(6-(4- (methylsulfonyl)phenyl)pyridin-2- yljurea? ACK A A A RJ N nNCi 8 / , A 0' "0

[0089] 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 (III):Attorney Docket No. PTZ-011WO(H2)por a pharmaceutically acceptable salt thereof, wherein:R1is selected from the group consisting of H, C1-C3 alkyl, Cl, F, CN, and O-C]-C6alkyl 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 C]-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, ary! -heteroaryl, and sulfonamide, wherein the (1) Ci-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, NR3R6, 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, C1-C3 alkyl-OH, C C3alkyl-O-Ci-C3alkyl, C(O)OR5, C(O)NR5R5, NR5R5, and N5-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 Cj-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 independentlyAttorney Docket No. PTZ-011WOselected from the group consisting of F, OH, and NR5R6, (ii) C3-C6cycloalkyl 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, C1-C4 alkyl, 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)NR5Rb, OR5, NR5Rb, oxo, SO2Rb, a 4- to 6-membered heterocyclic ring, and Ci-C4alkyl optionally substituted with one or more groups each independently selected from the group consisting of F, NR5Rb, 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) aryl-heteroaryl is optionally substituted with C1-C3 alkyl that is optionally substituted with OR5;R5is independently H or C C5alkyl;R° is 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:(5)-l-(8-fluorochroman-4-yl)-3-(5-(tetrahydro-2 / / -pyran-4-yl)thiazol-2-yl)urea, 1 -( chroman-4-yl)-3 -(4-cycl obutylthi azol-2-yl)urea,l-((3A,4A)-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.

[0090] In some embodiments, the compound of formula (III) is a compound listed in Table 3.Attorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -(CS')-8-chl orochroman-4-yl )-3 - (2-(l - oA| o hydroxyethyl)thiazol-4- yl)urea IlZOH Cl¥ V N J HkJHl-((S)-8-chlorochroman-4-yl)-3-(2- o' A 0 r-- J OH ((R)- 1 -hydroxy ethyl)thiazol-4-yl)urea(C6) CL, Isf A A ' N' ¥ r ' N \ j J H 1 iQ1 -((5)-8-chlorochroman-4-yl)-3- (2-(l - / cr'k o hydroxyethyl)thiazol-4- yl)ureaCl II A z x AOHA[1 J H Hpz zl-((S)-8-chlorochroman-4-yl)-3-(2- o rZ J OH ((S)- 1 -hydroxy ethyl)thi azol -4-yl )urea A-Z (C7) cf Ak" X'J1AH k hAi1 -[(45)-8-chlorochroman-4-yl ]-3 - [2- (dimethylamino)thiazol-4- yl]urea A' jClxzA O X / '- A H A irX A~~N 1I A N K N \H H X Z T t A / 1 -| (45)-8-chlorochroman-4-yl ] -3 - [4 - [ 4- 9 7 0 s— H [pyrrolidin-2- yl]phenyl]thiazol-2-yl]ureaJI A >~X I A k N 'N N A 1 kA H H ~~ l-[(45)-8-chlorochroman-4-yl]-3- [4-[4- [pyrrolidin-2- yl]phenyl]thiazol-2-yl]urea1 -(2-(l -(2-aminopropyl)-IHpyrazol- O’A 0 < 8 N z-v. * z 3-yl)thiazol-4-yl)-3-((5)- A J. I 1 JA Y T 8-chlorochroman-4-yl)urea 'N 'N' 'N Y-*- NH2X H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -(2-(l -(2-aminopropyl)-IHpyrazol- 3-yl)thiazol-4-yl)-3-((5)- CK A A $ / / ~~~^ T 8-chlorochroman-4-yl)urea Y Yr -hr " NAH H(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-( 1 -ethyl- 1 H-py razol -4-y 1 ) □’"'A O $thiazol-4-yl)urea cixA J,. JI X-XX" 'Y " N N' 'N W-N ’I A H H(5T)-l-(8-chlorochroman-4-yI)-3- (2- ( y o< c- / AA ’A O r rA N -A(pyridin-2-yl)thiazol-4-yl)ureaC OK / A. X,ZA ALu r N" " N"H Hu(5)-l -(8-chlorochroman-4-yI)-3- (2- ° / r,(pyridi n -4-yl)th iazol -4-yl)urea (A A o rAr. 1 1 JI X A p H H(5)-l-(8-chlorochroman-4-yl)-3- (2- phenylthiazol-4-yl)urea \T(5)- 1 -(8-fluorochroman-4-yl)-3 -(2- A q phenylthiazol-4-yl)ureaJ 1 A > A^> H H(5)- 1 -(chroman-4-yl)-3 -(2 -phenyl thiazol- 4-yI)urea px'A o A \ / / Vs I A~N N \=zH HA(5T)-l-(8-chlorochroman-4-yl)-3- (2- (pyridin-3-yl)thiazol-4-yl)urea0ASx / ~~Nct I J J-L A A~~~A Y |i JH HAttorney Docket No. PTZ-011WO xT Table 3 ^7 owc / O-' Chemical Name Structure1 -[(45)-8-chlorochroman-4-yl ] -3 - (2- VAk o" ' cyclopropylthiazol-4-yl)ureaJ w rCk U / .A< o=\l-[(45)-8-chlorochroman-4-yl]-3- [2-(l-methylpyrazol-4-yl)thiazol- O u4-yl]urea O-x AV-- if " N YN H 1 / V ( XYAJ o--' " J U My / .....■ ' ' n FT..w / ( } o.1 -| (45)-8-chlorochroman-4-yl ] -3 - [2-(4- methylsulfonylphenyl) thiazol-4-yi]ureaCK J J A JI H J H H Ol-[(45)-8-chlorochroman-4-yl]-3- [2-[4- (methyl sulfamoyl) phenyl] thiazol-4- yljurea Ck._1 -[(451)-8-chlorochroman-4-yl] -3 - [2 -(3 - methylsulfonylphenyl) thiazol-4-yl]ureaClx4-|4-[[(4S)-8-chlorochroman-4- yl] carbamoylamino ] thiazol-2-yl ] - N~Ckmethyl-benzamidexrf '" N' 'N" 'N| J H H 0 5-|4-[[(4S)-8-chlorochroman-4- 9 'i 2 / ryl] carbamoylamino ] thiazol-2-yl ] - TV-M\ NH—CK A J,. Amethyl-pyridine-2 -carboxamidefr 'v 'N N N x.~ / v I J H HN0 1 -| (45)-8-chlorochroman-4-yi ] -3 - [2 - [ 3 -0HN— (methylsulfamoyl) phenyl]thiazol-4- X. yljurea O' '’k O r'”® 0Ck. s. X A JL Ak A" N-' ' N N LA J JH HAttorney Docket No. PTZ-011WO N < XTable 3 r Chemical Name Structuremethyl 4-[4-[[(4S)-8- chlorochroman-4-yl] z carbarn oyl am ino]thiazol-2-yl ] -2-? '1 9 HUfluorobenzoate CK A AZk A / A r >-<< || J H H 0 X4-[4-[[(4S)-8-chlorochroman-4-yl]carbamoyl ammo] thiazol-2-yl]-2- methoxy-benzamide zz\ / 4-[4-[[(4S)-8-chlorochroman-4-yl] \ / —carbamoylamino] thiazol-2-y 1] benzamide o / Y K [1 \ / CK fHao " NZX 1 J H H " O i >o-- \ A! / 4-[4-[[(45)-8-chlorochroman-4- 7 \ \ / yl]carbamoyiamino]thiazol-2-yl]- 2- 0Xjj Q / T** M M methoxy-benzamide f 1 J. T-yr Jl -N- 41 -W WA X’ A V2H O -■ / H 0 X4-[4-|[(45)-8-chlorochroman-4- A J y 1] carbamoy lamino]thiazol -2-yl] - 2 -fl uoro- "1 II 7 AS, >- benzamide ar.NH21 J. Jl A — i V X — Z f V 'hr " N' N \\ 1 I J H H o S f XJ-' ' l-[(45)-8-chlorochroman-4-yl]-3- [2-(l-methylpyrazol-3-yl) thiazol- o' > o A;Xo„ 4-yl]urea ci 1 J J A 7 * i |l J H H1 -[(45)-8-chlorochroman-4-yl] -3 - [2-(4- cyanophenyl)thiazol-4- yl]urea 9^1 9 rVCK JL J-, A A.4— LA A IM N v / ~~NH H5-[4-|[(45)-8-chlorochroman-4-yl]carbamoylamino]thiazol-2- yl]pyridine-2- carboxamide1 -[(45)-8-cblorochronian-4-yl] -3 - [ 2- [ 1 - O’ or'S,P(2,2-difluoroethyl) pyrazol- 4-yl]thiazol-4- CK A J JI li A-, AN' VFyljurea Hsr ' - N F X H H FAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -[(4;S,)-8-chiorochroman-4-yl] -3- c ■) r--S[2-[ 1 -(2,2.2-trifluoroethyl) pyrazol-4- CK 1 1 AF yl]thiazol-4-yl]urea AA 'N' 'N V'N F I H Hcixl-[(45)-8-chlorochroman-4-yl]-3- [2-(5- 0 8cyano-2-pyridyl)thiazol-4- yl]ureacis. A,, B ll X / \'■'N"' N t. A1 J H HN" •'1 -[(45)-8-chlorochroman-4-yl] -3 - [2-[ 1 - 0 '(2,2-difluoroethyl) pyrazol- 3-yl]thiazol-4- CIs^ Iyljurea 1. 'hl A N AZ N A vr'-'- 7' I F H H1 -[(45)-8-chlorochroman-4-yl] -3- (A[2-[ 1 -(2,2,2-trifluoroethyl) pyrazol-3- Cl^ A A* X < t'r y 1] thiazol-4-yi ] urea Ay- " W" 'N' 'N A’ F H H1 -[(45\ 8^hlorochroman A-yl] -3 - [4-(4- CTAcyanophenyl)thiazol-2- yl]urea 0 S" A / =->CK A J.V ■ Y N ' 'NIxH H(l-[(45)-8-chlorochroman-4-yl]-3- [4-(4-methylsulfonylphenyl)thiazol-2-yl]ureaCl's. "N0 y J H Hl-[4-[4-(l-amino-l-methyl-ethyl)A o S-'A y---, phenyl]thiazol-2-yl]-3-[(45)-8- CR -k A A As 'V / chlorochroman-4-yl]urea xy" Y' 'hr ''N V NH?H H "1 - [2- [ 1 - [2-aminopropyl]pyrazol-4- yl]thiazol-4-yl]-3-[(45)-8- Ci-XJI Ji X T chlorochroman-4-yl]urea A / 'N' 'N \^N NH2H H1 - [2- [ 1 - [2-aminopropyl]pyrazol-4- O r" S..... yl]thiazol-4-yl]-3-[(45)-8- L A 1 A- / A A chlorochroman-4-yl]urea N N' N ■'■..•.■■N NH2H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-[(45)-8-chlorochroman-4-yl]-3- [2-[4-[pyrrolidin-2- 1 0 r'SHyl]phenyl]thiazol-4-yl]urea 1. A JL K / S w 'N 'N J H Hl-[(45)-8-chlorochroman-4-yl]-3- [2-[4-[pyrrolidin-2- > 0 r-s— -HO J. Ji / > yl]phenyl]thiazol-4-yl]urea K ''N' ' N' 'N K / V 1[j' H HA (1 -((5)-chroman-4-yl)-3 -(2-( 1 - hydroxyethyl)thiazol-4-yl)ureaQ J 1 n rSk / 0HfY " N'> SN'^NZA* A A H H1 -((5T)-chroman-4-yl)-3 -( 2-( 1 - hydroxyethyi)th iazol -4-yl)ureaA 1 H 1 / OH[i N N 'N \ KA H H(5)-l-(8-chlorochroman-4-yl)-3- (2- O'' O r-A.(pyrrolidin-1 -yl)thiazol-4- yl)urea 1Ck x. A S,. V J. Ji JI / -N "1 j H Hl-((tS)-8-cblorochroman-4-yi)-3- (2-(3- O' "hydroxy-3 -methyl pyrrolidine- 1 -yl)tb iazol - 4-yl)urea X A J Kr 'N" N v- ■'V-'OH H Hl-((5)-8-chlorochroman-4-yI)-3- (2-(3- cA" 0 s"S\hydroxy-3-methyl pyrrolidin-l-yl)thiazol- 4-yl)urea CK. A A 3" N' N" NH H \ l-((, S)-8-chlorochroman-4-yl)-3- (2-((5)-3- Q irA methoxypyrrolidin-1- yl)thiazol-4-yl)ureaX. Z5"' N! N "bT " N \H HVAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -((5)-8-chlorochroman-4-yl)-3- (2-((7?)-3- methoxypyrrolidin- 1 - yl)thiazol-4-yl)urea0.. A A Z " N / *N W N VA H H(5)-l -(8-chlorochroman-4-yI)-3- (2-(3,3- difluoropyrroli din- 1 -yl ) thiazol-4-yl)ureaCK Xl-((5T)-8-chlorochroman-4-yI)-3- (2-((i?)-3- 0.r-" Shy droxypyrrolidin - 1 - yl) thi azol-4-yl )ureax.. A X / -NY'N' K " N V-A } ( o —H H X0H y x - l-((5)-8-chlorochroman-4-yl)-3- (2-((5)-3-hydroxypyrrolidin-l -yl) thiazol- 4-yl)urea Ix, A A A-NZ"1 N N " N \ _HVO: Hl-(CS)-8-chlorochroman-4-yi)-3- (2-(3- o rA ■■ ■■ hydroxy-3 -(trifluoro methyl)pyrrolidin- 1 -. L I Z-N' I yl)thiazol-4- yl)urea CK •" A "hr'SN v-AH H ' X--"-?HOp f\ r l-((5)-8-chlorochroman-4-yl)-3- (2-(3- hydroxy-3 -(trifluoro methyl)pyrrolidin- 1 -0rs\ z1 Ji N ] yl)thiazol OK.... T J-4- yl)urea " N'" " N V-<H H >HO K O 'FF(. S')- 1 -(8-chlorochroman-4-yl)-3- 9" O r— s(2-( 1 -(oxetan-3-yl)- lH-pyrazol-4-. / "9C A A 9: $ / 'bZ yl)thiazoi-4-yl)urea( J Y Y < W(5)-l-(8-chlorochroman-4-yi)-3- (2-(3- fluoro-4-(methylsulfonyl) phenyl)thiazol- O'""^ o r'sy O 4-yl)urea X 1 A Z ' X z!-~~s — CKzr '-N' w x I H H o (5)-l -(2-(4-((2-aminoethyl)sulfonyl)phenyl)thiazol-4-yl)-3-(8- z'i 1 A A 'S, ° - •• / ""NH2 chlorochroman-4-yl)ureaC!xAz zr N N V_ / »( JHH OAttorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-((< S)-8-chlorochroman-4-yl)-3- ■ NH (2-( 1 -(pyrrolidin-3-yl)- 1H- pyrazol-4- O' Z O rA -v, Z? yl)thiazol-4-yl)ureacz i. it / i z— / 'N"\:=:=N H Hl-((5)-8-chlorochroman-4-yl)-3-. NH t (2-(l-(pyrrolidin-3-yl)-U7pyrazol- o' ''A 0 rZ Ji. / 4-yl)thiazol-4-yl)ureaCK 1 ii £ / --ZNH H(S)- 1 -(8-chlorochroman-4-yl)-3- 0 0 5 S _... (2-( 1 -methy 1 - 1 H- 1,2,3 -triazol -4- yl)thiazol-4-yl )urea C! A 1 Z V T T 1 XN'A (S)- 1 -(8-fluorochroman-4-yl)-3-(2- Zvo ( 1 -(tetrahydro -277-pyran-4 -yl )- 1 H- ° z0■pyrazol-4-yl)thiazol-4-yl)urea R { I. Isj- _ Z • z Z. J Z'x J H H(S)- 1 -(2-( 1 -ethyl- l / 7-pyrazol-4- yl)thiazol- 4-y l)-3 -(8 -fl uoro chroman-4-yl)urea'ft Av A AJ N & Z ' M \ / I H H(5)-l -(8-chlorochroman-4-yl)-3- (2-(4- o '~z o zsy O ((trifluoromethyl) sulfbnyl)phenyl)thiazol- j j II i v * 4-yi)urea r VS A W; H Hb: G-v •F1 F (S)- 1 -(8-chlorochroman-4-yl)-3- O ' 0 r-S O (2-(4-((2-(methylamino)ethyl) Civ. j i II i‘ A--Z \ y / -" N Xsulfonyl)phenyl)thiazol-4-yl)urea t; J H H 6 l-((5)-8-chlorochroman-4-yl)-3- - Q (2-(l -(tetrahydrofuran-3-yl)-lH- pyrazol- ox'z4-yl)thiazol -4-yl)urea z 9CR.. j. 1. A. / " Z''hl'' '■ N' " N WNH HcAttorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3- r°x(2-(l -(tetrahydrofuran-3-yl)-lH- pyrazol- A o r-'A4-yI)thiazol -4-yI)ureaCK I J 1 J XX A WN H H(5T)-l-(8-chlorochroman-4-yI)-3- (2-(4- methylpiperazin-1 -yl) thiazol-4-yl)ureaClxr A "hr 'hr 'N \ / I JH Hl-((< S)-8-chlorochroman-4-yl)-3- Y'X o rs / "x (2-((7?)-3 -hydroxypiperidin- 1 - y l)thiazol-4-! J JI 1yl)urea a ZXN;>XYX ’X N' " N X / I H H \ OH(5)-l-(8-chlorochroman-4-yi)-3- (2- o "" X o r's / — \ (piperidin- 1 -yl)thiazol-4- yl)ureaCR X X. JL X;Y 'V " N 'hr NJHH(5)-l-(8-chlorochroman-4-yl)-3- (2- o^'X o rA / — \ morpholinothiazoi-4-yl)ureaCR X X- X X / K f Y X w 'hr 'N xx J H H(1S)-l-(8-chlorochroman-4-yl)-3- (2-(4- O- o rx — O (dimethylphosphoryl) phenyl)thiazol-4- C. 1.1, 1,1 XX Xx yl)urea Y 'Y' N' 'hr 'N;1 J H Hs.:(5T)-l-(8-chlorochroman-4-yI)-3- (2-(l- X X o. XA cyclopropyl- lH-imidazol-4- yl)thiazol-4- yl)urea (CIO) Cl\ A X, X ¥ XXir x 'N' ifnKx ii n H(5)-l-(8-chlorochroman-4-yl)-3- (2-(5- D: 0 ff A / Ssn 0 (methylsulfonyl)pyridin-2- yl)thiazol-4- a. X,. A.,1 J. 1.. 4 yl)urea ¥ k V 'N t ¥ 'X 0, JH H6Attorney Docket No. PTZ-011WOTable 3Chemical Name Structure / A O (. S')- 1 -(8-chlorochroman-4-yl)-3- CA’Y O s-S. Ik., / (2 -(2 -methyl -227- 1,2,3 -triazol-4- 1 i f [1 >!!?. _ A N yl)thiazol-4-yl)urea f "'W'" N N \J H HA1 -((, S)-8-chlorochroman-4-yl)-3- (2-(2,2,2- 0^' "o 0 r-A pH trifluoro- 1 -hydroxy ethyl)thiazol-4-yl)urea 1 il A—- / Cl., A A A A -z|[ A AT 'hr' " N \ p H HrF F1 -((5)-8-chlorochroman-4-yl)-3- (2-(2,2,2- < O.(AY 0 pH trifluoro- 1 -hydroxy ethyl)thiazol-4-yl)ureaCl,1: M M / \ ’ w. • n n / \FF1 -( (S) -8 -chlorochroman-4-yl) -3 - O' " ''(2-( 1 -(2 -hydroxypropyl)- 122- pyrazol-4- X rArrA yl)thiazol-4-yl)urea ■'N' / N \:::44 OH H H X / $1 -( (S) -8 -chlorochroman-4-yl) -3 - O'"'"''-' co(2-( 1 -(2 -hydroxypropyl)- 122- pyrazol-4- Y j yl)thiazol-4-yl)urea A. / r / 1 -((5)-8 -fluorochroman-4-yl)-3 -(2 - ( 3 - \O" 1 ohydroxypyrrolidin-l-yl) thiazol- 4-yl)urea, s / < U. «• K J. 11. JI H" N \ — \ H H OH'll(5)- 1 -(8-chlorochroman-4-yl)-3- (2 -(4-((2 -(dimethyl am ino)ethyl) OK.sulfonyl)phenyl)thiazol-4-yl)urea 1!(5)-l-(8-chlorochroman-4-yl)-3- (2-(2-0 r-S OH hydroxypropan-2-yl) thiazol- 4-yl)urea AA A AAN ’ N' ‘NH Hl-(2-(l-amino-2,2,2- 0 NH2trifluoroethyl)thiazol-4-yl)-3-((2?)- 8- chlorochroman-4-yl)urea CK „?N A W A / N AsFH H ArF FAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure j 1 -((i?)-8-fluorochroman-4-yl)-3- (2-(3- c o c hydroxypyrrolidin- 1 -yi) thiazol-4-yl)urea - i / :H,,. J A A hr A NN " Z’A v.4xH H OHI1 -(2-( 1 -aminoethyi)tbiazol-4-yl)- 3-((7?)-8- ’“x. > 0 r ■ 9 NH chlorochroman-4-yl)urea o2 / xCK i - A. IL 1■"hr " N ' " NH H1 -(2-( 1 -aminoethyi)tbiazol-4-yl)- 3-((7?)-8- chlorochromaii-4-yl)urea oj1 -((^)-chroman-4-yl)-3 -(2-( 1 - IZhydroxyethyi)thiazoi-4-yl)urea% MMMf WMM JH1 -(( / ?)-8-fl uorochroman-4-y i )-3- (2-( 1 - hydroxyethyl)thiazol-4- yl)urea A o rA pH 1 I'N * \ H H1 -((7?)-8"flaorochromaii-4-yl)"3- (2-( 1 - hydroxyethyl)thiazol-4- yl)urea 0 o rA OH H 1 / A — <" N N \ U nS M n1 -((5)-8-fIuorochroman-4-y3 )-3 -(2- ( 1 - hydroxyethyl)thiazol-4-yl)urea y" O r --SV \,0H L A A?N' 'N ' " NH HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -((5)-8-fluorochroman-4-yl)-3 -(2- ( 1 - hydroxyethyl)thiazol-4-yl)urea Y Y II \ pH1) H H '(5)-l -(8-cblorochroman-4-yl)-3- (4-(4- (cyclopropylsulfonyl) phenyl)thiazol-2- CK I,1 A A AA... f.. yl)urea 'IJ H H. - 6 (5)-l-(8-chlorocbroman-4-yl)-3- (4-(4- A""''] 9 YA 9 / (etbylsulfonyi)phenyl) thiazol-2-yl)ureaCl\H H 0 1 -((, S)-8-chlorochroman-4-yl)-3- (4-(4-(S- o" Y o S"‘k / ■---A o methylsulfonimidoyl) phenyl)thiazol-2- C!xx-k A. A 2 — 4— - yl)ureaj J H H HN l-((, S)-8-chlorochroman-4-yl)-3- (4-(3-(S- x A methyl sulfonimidoyl)phenyl)thiazol-2- yl)urea O'" A o s-'ACK -X i 1 1 A W 1''hT 'N V / | J H H{. S')- i -(8 -chlorochroman-4-yl)-3 - (4-(5 - (methylsuifonyl)pyridin-2- yl)thiazol-2- 9 9"' \ p Ck yl)urea xI, / " A-- H HN- □ l-((5)-8-chlorochroman-4-yl)-3- (4-(3 -(N, 1 -dimethyl- 1 -pheny 1 -?,6- \: N s.: sulfanediimine) thiazol-2-yl)urea 0 S'" A x— < 'NH CK," N" JI " N”' A 'N > A V. / ' H Hl-((5)-8-chlorochroman-4-yl)-3- P (4 - (3 - ( 1 -oxido-4-oxo-3,4-dihy dro- A27 / - 116,2, 5 -thiadiazol- 1 - CK ii S-XZyl)phenyl)thiazol-2-yl)ureao '' Y 9 y \ _ / " AHA J KA V / H HAttorney Docket No. PTZ-011WOV' Table 3!.1, ■ A Chemical Name Structure(5)-l-(8-chlorochroman-4-yl)-3- (2- o' A o rt ' (iso rop lamno) hia! A p y i t zol-4- yl)ureac VI 1 i L O C ' ' J / k-NH kA1] J H H / (5)-l -(8-chlorochroman-4-yi)-3- (2-( 1 - ck A,x o n x- methyl- 127-imidazol-4-yl) thiazol-4- yl)urea J. 11 1 ¥x\ / .’ArXNX" NH H1 -((5)-chroman-4-yl)-3 -(2-(3 - o " ' ■ o rA hydroxypyrrolidin- 1 -y I) thi azol-4- yl)urea 1 / \ 1 1 1 J O „ A AT N] A # \ y. H H OH 1 -(CR)-8-dilorochroman-4-yl)-3- (4-( 1 - / vhydroxyethyl)thiazol-2- yl)urea (Xi 0 S-'-'X pH c 4,1 J. I kX V 'vh \To= / JxhT " N \ H H\1 -((i?)-8-chlorochroman-4-yl)-3- (4-(l- hydroxyethyl)thiazoI-2- yl)urea 0 A A., pH Jc ik X A V 1 '" N' A " N' X N W \ [| J AH H " " O V x l-((7?)-8-chlorochroman-4-yl)-3- (2-(cyclopropyl(hydroxy)methyl)thiazol-4-yl)urea CKl-((7?)-8-chlorochroman-4-yl)-3- O'" A C> • S QH (2-(cyclopropyl(hydroxy)J. n i methyl)thiazol-4-yl)urea Clx A " ' M ' - " N " " N \k nJ k nJ ijk > (5)- 1 -(8-chlorochroman-4-yl)-3 - (2-(4-cyanophenyl)-5-methylthiazol-4-yl)ureaAttorney Docket No. PTZ-011WO Table 3Y Z o..Chemical Name Structurei(5)- 1 -(8-chlorochroman-4-yl)-3 - Y- (4-(4-cyanophenyl)-5-methyl / \thiazol-2-yl)urea1 -((5)-8-chlorochroman-4-yl-4-< / )- oYY o3 -(2-((7?)- 1 -hy droxy ethyl-2, 2,2- < A)thiazol-4-yl)ureaCiX - Y ' 'N ' ' 'YH b} < °>.1 -((5)-8-chlorochroman-4-yl-4-< / )- g 1 o r'Y pH 3 -(2-((5)- 1 -hy droxy ethyl-2, 2,2- / < A)thiazol-4-yl)urea CkYY YY '" N \ Y X H H / \ J.zA / u\ / D D (5)-l-(2-(acetyl-r / 3)thiazol-4-yl)-3- (8-chlorochroman-4-yl-4-r / )urea 9'X'Y Y o.o Cl\ X k / x x 1 1H H sNX-D Z A x o b (5)- 1 -(8-chlorochroman-4-yl)-3 - / (2-vinylthiazol-4-yl)urea cY " Y c >,f's\Ck.. 1. J 9 f! Y X '" N A % IHH Y " Q' D"A X1!! (5)- 1 -(2-acetylthiazol-4-yl)-3 -(8- ) S chlorochroman-4-yl)urea ox"1CkxI 1 -, / '■-xW " N \\ H H 0 (5)- 1 -(8-chlorochroman-4-yl)-3 - 'X.(2-(3,3 -difluorocyclobutane- 1 - i’*' 1carbonyl)thiazol-4-yl)urea s''Attorney Docket No. PTZ-011WOTable 3Chemical Name Structure(5)- 1 -(2-(bicy clo [ 1.1.1 ]pentan- 1 - (yl)thiazol-4-yl)-3-(8- 0 f A chlorochroman-4-yl)urea Ci.,,x. x’. 1 1"■'N' '" N"' " N """> H H1 -(2-(bicyclo[l.1.1 ]pentan- 1 - O’"' " P O OH yl(hydroxy)methyl)thiazol-4-yl)-3- ((5)-8-chlorochroman-4-yl)urea CK X. J 1 JL H■*-...oP H H Z "= / 1 -(2-(bicyclo[l.1.1 ]pentan- 1 - (yl(hydroxy)methyl)thiazol-4-yl)-3- o PH((5)-8-chlorochroman-4-yl)ureaCi\ s', J JL J / >-;{v N‘ N‘ N V O J'"H Hp (S)- 1 -(2-(bicyclo [1.1.1 ]pentane- 1 - O r-'P p carbonyl)thiazol-4-yl)-3-(8- chlorochroman-4-yl)urea Cl\ J 1''N '" " N \ H H p l-((5)-8-chlorochroman-4-yl)-3- 0"" ' 0 rA pH (2-((3,3- difluorocyclobutyl)(hydroxy)meth Cpf A p-",1 1, kN / Y \ yl)thiazol-4-yl)urea H H / "7 ‘ix / > F l-((5)-8-chlorochroman-4-yl)-3- O' A 0 Y'P pH (2-((3,3- difluorocyclobutyl)(hydroxy)meth Cp.1. J, J Ir" "p" 'N " W" 'N * \ yl)thiazol-4-yl)urea | H H / "" AF(A) - 1 - (2 - ( 1 -acetylazeti din-3 - Cyl)thiazol-4-yl)-3-(8- > ' 'P Q A'"® chlorochroman-4-yl)urea Cl-Xp' J, " IM'".1 Ji / " N' N < P—J H H A OAttorney Docket No. PTZ-011WO....-. O Table 3i Chemical Name Structurel-(2-acetylthiazol-4-yl)-3-(8- chloro-4-methylchroman-4-yl)urea 1 08 0xCl-... 1 1" A "hT 'NH z H\ O=l-(2-acetylthiazol-4-yl)-3-(8- / / chloro-4-methylchroman-4-yl)ureaC1 -(2-acetylthiazol-4-yl)-3 - ((37?,47?)-8-chloro-3- 0 o -- -A o methylchroman-4-yl)urea c I A A / A f Ar AT 'N \ H Hl-((5)-8-chlorochroman-4-yl)-3- O'""' o x-S OH (2-(l -hydroxy ethyl- 1,2,2,2- c / 4)thi azol -4-yl )urea Cl X' 1 1A. A ' N VnH H A °D b 1 -(2-acetylthiazol-4-yl)-3 - ((25,45)-8-chloro-2- Xmethylchroman-4-yl)urea cA t o rA p 1 J] ii A--A cH H1 -(2-acetylthiazol-4-yl)-3 - ((35,45)-8-chloro-3- A o < ■S0 methylchroman-4-yl)urea c 1 JI 1U H M H1 -(2-acetylthiazol-4-yl)-3 - ((27?,45)-8-chloro-2- methylchroman-4-yl)urea O''""""- 0 ' A O c.. 1 I / -A;,W' " N ” ’N \ H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -(2-acetylthiazol-4-yl)-3 - ((35,4K)-8-chloro-3- Ck O 0 methylchroman-4-yl)urea i I i i wj H H1 -(2-acetylthiazol-4-yl)-3 - ((37?,4S)-8-chloro-3- omethylchroman-4-yl)urea 1 i Yi ACCk„.. A Y r \VN' " NT " N \ H Hl-((5)-8-chlorochroman-4-yl)-3- (2-( 1 -hydroxy ethyl- 1,2,2,2- O'xc / 4)thi azol -4-yl )urea Cl-^. 1 1 XkDr Y Y "N' Y°□ D l-((5)-8-chlorochroman-4-yl)-3- (A(2-( 1 -hydroxy ethyl- 1,2,2,2- O Y’® 9Hr. c / 4)thi azol -4-yl )urea Ck.^jx,... A AYr "bT " N v.nH H / \DD D l-((5)-8-chlorochroman-4-yl)-3- (2-(2-,.o (methoxymethyl)cyclopropyl)thiazol-4-yl)urea A A 0 rA A*1 J 1 M A '"fck V N HH Hl-((5)-8-chlorochroman-4-yl)-3-0H(2-( 1 -(3 -hydroxy cyclobutyl)- UTpyrazol- 4-yl)thiazol-4-yl)urea(X X - I J. AA A' * ■' " M' N ■ NT J k H(5)-l-(2-(acetyl-< A)thiazol-4-yl)-3- 0""(8-chlorochroman-4-yl)urea 0 Y® -0 Ck 1 1r " N" " N v_nH H / \uD DAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure (AS')- 1 -(8-chlorochroman-4-yl)-3 - (2-( 1 -(3,3 -difluorocy clobutyl)- UTpyrazol- 4-yl)thiazol-4-yl)ureal-((5)-8-chlorochroman-4-yl)-3- (2-(l -hydroxy ethyl-2, 2,2- cA)thiazol-4-yl)ureal-((5)-8-chlorochroman-4-yl)-3- (2-(l -hydroxy ethyl-2, 2,2- cA)thiazol-4-yl)ureal-((5)-8-chloro-6- (trifluoromethoxy)chroman-4-yl)- 3-(2-(l -hydroxy ethyl)thiazol-4- yl)ureal-((5)-8-chloro-6- (trifluoromethoxy)chroman-4-yl)- 3-(2-(l -hydroxy ethyl)thiazol-4- yl)ureal-((5)-8-chlorochroman-4-yl)-3- (2-(2- (hydroxymethyl)cyclopropyl)thiazol-4-yl)ureaAttorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-((5)-8-chlorochroman-4-yl)-3-... OH (2-(2- (hydroxymethyl)cyclopropyl)thiaz C A 'A o A A ol-4-yl)ureaCi J 1 1 YY- A " A" Ar' AHzi H H“•Xl-((5)-8-chlorochroman-4-yl)-3-. OH (2-(2- (hydroxymethyl)cyclopropyl)thiaz ( A o A ol-4-yl)urea |j 4Ci......r'" AA ' N’ " ' NH"' i H Hl-((5)-8-chlorochroman-4-yl)-3-... OH (2-(2- (hydroxymethyl)cyclopropyl)thiaz 0'"' A o ■■sA ol-4-yl)ureaCi\ A\ X A X'hi HH H JV-(l-(4-(3-((5)-8-chlorochroman- 0 4-yl)ureido)thiazol-2- \ c II c y' 1 0 < -A HN-S-- yl)ethyl)methanesulfonamideJ-,.. A. A A o " W " N' N \ H H JV-(l-(4-(3-((5)-8-chlorochroman- 9 4-yl)ureido)thiazol-2- o '' A o < TAHN~~S — yl)ethyl)methanesulfonamideA A x o " N'- 'N \ H H(5)- 1 -(8-chlorochroman-4-yl)-3 - r" A (2-(5,6-dihydro-4 / f-pyrrolo[l,2- o'" A o r-A XA / ?]pyrazol-3-yl)thiazol-4-yl)ureaCK A J- A A. / ' ( 4 X; Y YNAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure(5)- 1 -(2-acetylthiazol-4-yl)-3 -(8- chloro-6- "k o — -s (trifluoromethoxy)chroman-4- V L A Ayl)urea x '*N" N" 'N \1 H H1k§J 32-(4-(3-((5)-8-chlorochroman-4- q. yl)ureido)thiazol-2-; ti U— '**** / A " « > " OH yl)cyclopropane-l -carboxylic acid Q O' A 0 k A / *;; j! ii X- <"i" N 'N' " Ni n H Hl-((5)-8-chlorochroman-4-yl)-3-f 0HO (2-( 1 -hydroxy ethyl- 1 -c / )thiazol-4- yl)urea Ck. J.. A A A A X X XT " N' NH Hk Jl-((5)-8-chlorochroman-4-yl)-3- (2-( 1 -hydroxy ethyl- 1 -c / )thiazol-4- ck A o -s.. yl)urea I V $ \ V-0 ck X A X # *\ x x x " NH H(5)- 1 -(2-acetylthiazol-4-yl)-3 -(8- chloro-6-methoxychroman-4- cyl)urea Ck.. 1. 1 I x" x 'X X " \H H■<)l-((5)-8-chloro-6- c x ■■■ Q, _ S methoxy chroman-4-yl)-3 -(2-( 1 - y it \ * PH hydroxyethyl)thiazol-4-yl)urea Z" AZz-'>"S"V-'A " N "' N '"'X \ H HJi }Attorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-((5)-8-chloro-6- o - — s methoxy chroman-4-yl)-3 -(2-( 1 - hydroxyethyl)thiazol-4-yl)urea 1 1 A- AHJ " N' 'Ar'' 'N \ H HA(R)- 1 -(2-acetylthiazol-4-yl)-3 -(8- chlorochroman-4-yl)urea cACkxL, i fAk' A-A v H H ' (5)-4-(3-(8-chlorochroman-4- (Ayl)ureido)thiazole-2-carboxylic 0 rA -P acid CkxA ■x-. A A X kr Ar" 'AH hmethyl (5)-4-(3-(8-chlorochroman- 4-yl)ureido)thiazole-2-carboxylate n''' A 0 'A 0? i °! / W kAA k A A v kJHl-((5)-8-chlorochroman-4-yl)-3- < A A o <-"ss. OH (2-(l,2-dihydroxyethyl)thiazol-4- yl)urea CK 1 X 1 A AkI(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-(6-oxo- 1,6-dihy dropyri din-3 - yl)thiazol-4-yl)ureaCK A, X A A / -< A 1 H Hl-((5)-8-chlorochroman-4-yl)-3- (AA 0 r" A,0H (2-(l,2-dihydroxyethyl)thiazol-4- yl)ureaC1\ J- X 1 A Ak| H H " OHAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure(5)- 1 -(8-chlorochroman-4-yl)-3 - o -—S, OH (2-(3 -hydroxy oxetan-3 -yl)thiazol- 4-yl)urea.. 1Ar" "'N J it ii ~~o(5)- 1 -(2-(azeti din-3 -yl)thiazol-4- yl)-3-(8-chlorochroman-4-yl)ureaA?" '' A'I A? A „NH - 'V -'N ’N N V i H H(5)- 1 -(8-chlorochroman-4-yl)-3 - 0^(2-(3-fluorooxetan-3-yl)thiazol-4- 0 ir-s-< x yl)urea Ci-. I 1 A-A X. X"*N'' 'N" " N i! H H —0 Q(5)- 1 -(8-chlorochroman-4-yl)-3 - O rr-'-'A(2-(oxetan-3-yl)thiazol-4-yl)urea i it A _ / \.cu... T'' J,. >1 \ SJ x- V" H H1 -(8-chloro-4-methylchroman-4- 0"" n r-S OH yl)-3-(2-(l -hydroxy ethyl)thiazol- 4-yl)urea. 1 Ji / --*<X'X' ' X \ H Hl-(8-chloro-4-methylchroman-4-yl)-3- o"' o OH (2-(l -hydroxy ethyl)thiazol-4-yl)urea fl JI \ * / JL c..." X ' X ' ’N \ I! Hl-(8-chloro-4-methylchroman-4-yl)-3- O '"' O pH (2-(l -hydroxy ethyl)thiazol-4-yl)urea.. 1 1 M v -x" " X \ H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-(8-chloro-4-methylchroman-4-yl)-3- O"' O AA OH (2-(l -hydroxy ethyl)thiazol-4-yl)ureax1 1A" AT 'N \ H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - £f' ~Y- ■A 0 PH (2-(l -hydroxy ethyl)thiazol-4-yl)urea / A« II \ * / t K _ \ / A / \ X \ / '" N‘ " N" N \ %, / / H H\ / _1 -(8-chloro-3 -methylchroman-4-yl)-3 - £(2-(l -hydroxy ethyl)thiazol-4-yl)urea o * PHC1.. A A X \ \H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - ().rA OH (2-(l -hydroxy ethyl)thiazol-4-yl)ureacu 1 A I Z-Y. N' 'N" 'N \ H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - (2-(l -hydroxy ethyl)thiazol-4-yl)urea o * -0H. 1 1''N’x'N \ H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - (2-(l -hydroxy ethyl)thiazol-4-yl)urea 0 A,,011Ck,.x1. 1 A'N' 'bP 'N X H H1 -(8-chloro-3 -methylchroman-4-yl)-3 - (2-(l -hydroxy ethyl)thiazol-4-yl)urea 9 iT’11s\ - PHCKXY A. A \ 'N' 'N' ’N \ H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - AX 0 fA. * 0— methoxyethyl)thiazol-4-yl)ureaCh... I 1 -N- 1 -N- 1NX 'll! H H(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- (A(methylthio)thiazol-4-yl)urea 11 1 A H A 'N" 'NI j H. H1 -((4S)-8-chl oro-3 -methylchroman-4- yl)-3-(2-(l -hydroxy ethyl)thiazol-4- AA' 0 / 0Hyl)urea i Ji 1Cl\ * \ H Hl-((4S)-8-chl oro-3 -methylchroman-4- if' Q rA OH yl)-3-(2-(l -hydroxy ethyl)thiazol-4- yl)urea ckxA A. A A / AxA'vhr N \ H H1 -((R)-8-chlorochroman-4-yl)-3 -(2-(l - hydroxyethyl)thiazol-4-yl)ureaCk. A*,. A.XA'A H H1 -((R)-8-chlorochroman-4-yl)-3 -(2-(l - hydroxyethyl)thiazol-4-yl)ureaCk X 1 1A" \ V * \ H 11 ’ vl-((4S)-8-chloro-2-methylchroman-4- yl)-3-(2-(l -hydroxy ethyl)thiazol-4- yl)urea A o r'S' 0HCkxX A A / AxA '" N N \ H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-((4S)-8-chloro-2-methylchroman-4- yl)-3 -(2-( 1 -hydroxy ethyl)thiazol-4- yl)urea o OH f 1 1 '" NT A A 1 'N A-r< \H Hl-((4S)-8-chloro-2-methylchroman-4- yl)-3 -(2-( 1 -hydroxy ethyl)thiazol-4- yl)urea0 f_-S OH, X A.1. l / x f X- N N’ N \H Hl-((4S)-8-chloro-2-methylchroman-4- yl)-3-(2-(l -hydroxy ethyl)thiazol-4- yl)urea O'X*V> 0 r""S% OH CRX1.1 Ajf '■'V ’" N' ''N".1 N \H H(S)- 1 -(8-chlorochroman-4-yl)-3 -(2- O'" OS- 0— (methoxymethyl)thiazol-4-yl)ureaC'K 1 V" J. " N JL. " N ' 1. N] H H2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- methyl cyclopropane- 1 -carboxamide(X O ■-" ■2 A* i il ii \ * / \ < A..„ A 4,.1 A.A'" "77"" ''Ar'" N ' ' N Hi f{ H2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- methyl cyclopropane- 1 -carboxamide T (X 0 ■-" ■2 A* i il ii \ * / \ < A..„ A J. 1 A. X —"" 'Xr' AR ' N Hi H HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure2-(4-(3-((S)-8-chlorochroman-4- °VNH2 yl)ureido)thiazol-2- yl)cy clopropane- 1 -carboxamide A| I!CK^ X, R f ■■■" V- / AA —X'' ’" V' ~N HH H1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - ( A" A ohydroxy-2-methylpropyl)thiazol-4- * OH yl)urea CR 1.. J. 1 1 A'A A ’N \ H H A1.1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - hydroxy-2-methylpropyl)thiazol-4- yl)urea CR A X A A A“A x A N N N v I J8" / ' 2-(4-(3-((S)-8-chlorochroman-4- i yl)ureido)thiazol-2-yl)-N- methyl cyclopropane- 1 -carboxamidey " A o rA| [) j. h CKxY "NZ*2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- °^NH methyl cyclopropane- 1 -carboxamide( A ~A 0. • -s. Z * CK^, J I. A X 1 x A '-x- A / :■ N N N H| H H2-(4-(3-((S)-8-chlorochroman-4- i yl)ureido)thiazol-2-yl)-N- methyl cyclopropane- 1 -carboxamide‘ f \ y\ J, A A1 N N HH HAttorney Docket No. PTZ-011WOTable 3Chemical Name Structure2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- yl)cy clopropane- 1 -carboxamide O'' O;r'A, • CK 'S 1 J. 1,1 AY Y' " N" ’N’ NH H(S)- 1 -(8-chlorochroman-4-yl)-3 -(2-(5 - O'" '''I 0 r-'Amethyl- 1 -(oxetan-3 -yl)- 1 H-pyrazol-4- ct. ) 1 y *yl)thiazol-4-yl)urea ' "'NT ' 'J H H / y —!■ () 2-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2-yl)-N- methyl cyclopropane- 1 -carboxamideO’"' o * A* 1 IL L' A-Y" N. urt n u1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - O'"hydroxypropyl)thiazol-4-yl)urea o pH |l fl ZX--Y CK„.. J'-'-.' ■XT N 'N \ H H / 1 -((S)-8-chlorochroman-4-yl)-3 -(2-(l - 0 OH hydroxypropyl)thiazol-4-yl)ureaCk^ 1 1 1H H / (S)- 1 -(8-chlorochroman-4-yl)-3 -(2-(3 - / '" O methyl- 1 -(oxetan-3 -yl)- 1 H-pyrazol-4- 1 o 'S.. A- J yl)thiazol-4-yl)urea J. 1 J y. / 'Y. 'N"’ NH H / (S)- 1 -(2-(4-(2-aminopropan-2- yl)phenyl)thiazol-4-yl)-3-(8- eu 1 i...chlorochroman-4-yl)urea JL Z. < MZ Y x..N- -NA / X | ] H H ” NHjAttorney Docket No. PTZ-011WOTable 3Chemical Name StructureN-(l-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- A A Q rA HN-V yl)ethyl)acetamide A A A # ~ \ b ''KY' V 'N' 'NH HN-(l-(4-(3-((S)-8-chlorochroman-4- yl)ureido)thiazol-2- A'A o rA A- / yl)ethyl)acetamide A A. A A. \ b Y"' '"'N A- 'N11 11(S)- 1 -(8-chlorochroman-4-yl)-3 -(2-( 1 - methyl-3 -(trifluoromethyl)- 1 H-pyrazol- (AX| 0 r'A z-s / 4-yl)thiazol-4-yl)urea Ck 1 X X X A-A T I T r Y rNA * p— A i \ (S)-l-(2-(2H-l,2,3-triazol-4-yl)thiazol- cA O ff NK 4-yl)-3-(8-chlorochroman-4-yl)ureaCl\ 1 1 JL A Ab " A A AN H H0(S)- 1 -(8-chlorochroman-4-yl)-3 -(2-( 1,3 - »-y Z'xs' dimethyl - 1 H-py razol -4-y 1 )thi azol -4- €f'"'yl)urea Cl\ 1 J 1. > A T / 'N'NH H / J(S)-4-(3-(8-chlorochroman-4- yl)ureido)thiazole-2-carboxamide[,1 ¥. A r A AN<nh^ (R)- 1 -(4-(3 -((S)-chroman-4- yl)ureido)thiazol-2-yl)pyrrolidine-2- (A \ 9 As\ AA carboxamide:rtI A / '~N. J A, / A" A A II H iO^\Nil,Attorney Docket No. PTZ-011WOTable 3Chemical Name Structurel-(2-(l-aminoethyl)thiazol-4-yl)-3-((S)- (A o NHI 8-chlorochroman-4-yl)ureaA... A 1 ZA ‘•'N' 'N' -NH H1 -(2-(l -aminoethyl)thiazol-4-yl)- O'"’3-((S)-8-chlorochroman-4-yl)urea o r'A NH,1 JA AZ "z * *> A N N \ H H(5)- 1 -(8-chlorochroman-4-yl)-3 - (2-(l-methyl-l / f-l,2,3-triazol-5- < A A o rA K yl)thiazol-4-yl)ureaC1\ i 1 11 / / X-X J '' "'N N X--N H H(5)-4-(3-(8-chlorochroman-4- yl)ureido)- / V-methylthiazole-2- (A O rA, P carboxamide CU, A A A' " A" Af’ 'NNH H HN-((R)- 1 -(4-(3 -((5)-chroman-4- O'" 0yl)ureido)thiazol-2-yl)pyrrolidin- r'\3 -yl)methanesulfonamide. X A~A / o A" 'z V-A V- || '] S H A-A H(5)-l-(2-(2-oxa-6- azaspiro [3.3 ]heptan-6-yl)thiazol-4- o'" 'A? r'V. xA\ / \ y 1 ) - 3 -(chroman-4-yl)urea IL A Xk JHHN-((R)- 1 -(4-(3 -((5)-chroman-4- yl)ureido)thiazol-2-yl)pyrrolidin-03-yl)acetamide X 1 JL,* o A ATVNX'NH Hv;.-'(5)- 1 -(8-chlorochroman-4-yl)-3 - O' A o A, / (2-((2- 1 methoxyethyl)(methyl)amino)thiaz J 1 / A'A'-x'A"' " A A V. ol-4-yl)urea H H / OAttorney Docket No. PTZ-011WOTable 3Chemical Name StructureN-((S)- 1 -(4-(3 -((«S)-chroman-4- D O \ Z-., yl)ureido)thiazol-2-yl)pyrrolidin- 3 -yl)methanesulfonamide A k. A „A J 01 T H H * V'K d k ii II 0 N-((S)- 1 -(4-(3 -((S)-chroman-4- 0 r-A yl)ureido)thiazol-2-yl)pyrrolidin- 1 1 JI 1 V-N o 3-yl)acetamide if ■'< 'N ' N / II H H X ' \ X k H 1 -((R)-chroman-4-yl)-3 -(2-(l - hydroxyethyl)thiazol-4-yl)ureaV / o% \> / y.........\ _ _

[0091] 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): x&r iFormula (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,Attorney Docket No. PTZ-011WOheterocyclyl, or substituted heterocyclyl;wherein A is connected to N via a C-N bond; and* denotes a chiral carbon.

[0092] 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 r i i JAAA 1 Ax A A. Z Al-[rac-(4S)-8-chloro-3,4-dihydro-2H- a A z^ pyrano[3,2-b]pyridin-4-yl]-3-[l-[rac- 1 A. / 1 (lR,3R)-3- hydroxycyclopentyl]pyrazol-3 - 1yl]ureal-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[l-[rac- A Is(lS,3S)-3-.x' Arv^-' JL. A '".'V / *S J hydroxycyclopentyl]pyrazol-3 - yl]urea1 -[2-( 1 -methyl-6-oxo-3 - pyridyl)thiazol-4-yl] -3 - [rac-(4 X A A A S) -8 - " 'X T A / chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]urea1. X Azz r 1 - [2-(3 -methyl- 1,2,4-thiadiazol-5 - yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- i 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea (C9)j T i i r \ / A l-[2-(6-oxo-lH-pyridin-3-yl)thiazol- A A A A A / A A 4-yl]-3-[rac-(4S)-8-(difluoromethyl)- S' '" W- 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name StructureN-methyl-6-[[rac-(4S)-8- J;(difluoromethyl)-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4- yl]carbamoylamino]pyridine-2- carboxamidel| i \ / 1 - [ 1 -(2-pyridyl)pyrazol -3 -yl] -3 - [rac- x- *(4S)-8-(difluoromethyl)-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea x ✓ Jr \l-[2-(2-methyltetrazol-5-yl)thiazol-4- L A 8Xyl]-3-[rac-(4S)-8-chloro-3,4-dihydro- J2H-pyrano [3,2-b] pyridin-4-yl] ureaS C UM - l-[(4S)-8-chloro-3,4-dihydro-2H- III. A i )>— / ' pyrano[3,2-b]pyridin-4-yl] -3 - [2 X '-(6 - oxo- lH-pyridin-2-yl)thiazol-4- yl]ureamethyl 3-[4-[[rac-(4S)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4- rx / yl]carbamoylamino]thiazol-2- i A / - V. A - yl]bicyclo [1.1.1 ]pentane- 1 - T "carboxylatel-[(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 -[ 1 -(6- oxo- lH-pyridazin-3 -yl)pyrazol-3 - Tyl]urea85^ I X- / l-[2-(4-methyloxazol-2-yl)thiazol-4- L J \ J [ a - 4 ) V 8iz' yl]-3- r c ( S -8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea1 -( 1 -pyridazin-3 -ylpyrazol-3 -yl) -3 - " Xx XA X-™ / [rac-(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structureh — / / \\ X %,1 - [ 1 -(4-pyridyl)pyrazol -3 -yl] -3 - [rac- H(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]ureal-[2-(5-fluoro-2-pyridyl)thiazol-4- ■x, v A, xr A*. $ A yl]-3-[rac-(4S) si ss x -8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea<: YCi xxi r V.H - \ l-[(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 - [2 -(6 - -x \ 0 methoxy-2-pyridyl)thiazol-4-yl]urea / oA X F Y,x < XY A \ l-[(4S)-8-methyl-3,4-dihydro-2H- '> Y -X -x i pyrano[3,2-b]pyridin-4-yl] -3 -[2-( 1 - methylpyrazol-3-yl)thiazol-4-yl]urea1 i^\ / ^\ L. X ) 1 - [ 1 -(3 -pyridyl)pyrazol -3 -yl] -3 - [rac- ■'A Ji'' 'k 4 (4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]ureaXx,»x1 - [2- [ 1 -(oxetan-3 -yl)pyrazol-3 - J-J yl]thiazol-4-yl]-3-[rac-(4S)-8-chloro- A iX k-r-< Ti'3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]ureax-A1 - [2- [ 1 -(oxetan-3 -yl)pyrazol-3 - yl]thiazol-4-yl]-3-[rac-(4R)-8-chloro- > J J. / -Y T Ax A* \sxJ3,4-dihydro-2H-pyrano [3,2- =4b]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure1 V1 t L Jk At i 1 -[2-( 1 -methyltriazol-4-yl)thiazol-4- yl]-3-[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea x J1 -[2-( 1,5 -dimethylpyrazol-3 - ii S k. / S / A, A Z '% i yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- 8 'rw3,4-dihydro-2H-pyrano [3,2- Ib]pyridin-4-yl]ureaX I Xs\ / ssssa^ 1 -[ 1 -(4-cyano-3 -fluoro- [ '■■■: - X phenyl)pyrazol-3 -yl] -3 - [rac-(4 S) -8 - A’"--. -^x A. A, / % / A J - » ch o o: x •<r’ Xl r - -. - / / -3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]urea1 -[ 1 -(2-oxo- lH-pyridin-4-yl)pyrazol- 3 -yl] -3 -[rac-(4S)-8-chloro-3,4- ";'- X. I A AA At dihydro-2H-pyrano[3,2-b]pyridin-4- t T * w yl]urea1 -[ 1 -(6-oxo- lH-pyridin-3 -yl)pyrazol- 3 -yl] -3 -[rac-(4S)-8-chloro-3,4-. ■'-^x X 1 1. / A s / A 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-[l-[rac- v A, A< A (lS,3R)-3- 'A \:•< X hydroxycyclopentyl]pyrazol-3 - AtiS ^.4yl]urea1 -( 1 -phenylpyrazol-3 -y 1) -3 -[rac-(4S)- 1, JI 1 I X / X > 8-(difluoromethyl)-3,4-dihydro-2H- 0 1pyrano[3,2-b]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structureo3.1.. O ---A l-[(4S)-8-chloro-3,4-dihydro-2H-Z f— 4 pyrano[3,2-b]pyridin-4-yl] -3 - [2 -(3 - X,f-jhydroxyoxetan-3-yl)thiazol-4-yl]ureao Z / . X ■> 1 -[2-( 1 -cyclopropylpyrazol-3- yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- •A L JL 1 > Y Y 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea1 - [2-(5 -methyl- 1,3 A-thiadiazolZ- ylXhiazoM-ylJ-S-frac-CdSXS-chloro- i y 1 'v I XT 1 H Y 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]ureal-[2-(6-oxo-lH-pyridin-3-yl)thiazol- A. A A Z A c 4-yl]-3-[rac-(4S)-8-chloro-3,4- XA 'X A™--, / dihydro-2H-pyrano[3,2-b]pyridin-4- Byl]urea\ / ■ l-[rac-(4S)-8-chloro-3,4-dihydro-2H- h fs' pyrano[3,2-b]pyridin-4-yl]-3-[l-[2- * '....,_s As. AX- X ~X, A[ 1 O ist'" —rac-( 1 R)-2,2,2-trifluoro- 1 -hydroxyIethyl] -4-pyridyl]pyrazol-3-yl]ureal-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[l-[2- sYAzl >[rac-( 1 S)-2,2,2-trifluoro- 1 -hydroxy^>1 ethyl] -4-pyridyl]pyrazol-3-yl]urea1 -[ 1 -(6-methoxy-3-pyridyl)pyrazol- 1 / A \ X — 73-yl]-3-[rac-(4S)-8-chloro-3,4- 'X" -A z V~~ / dihydro-2H-pyrano[3,2-b]pyridin-4- yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structureco1 -[ 1 -(2-methoxy-4-pyridyl)pyrazol- 3-yl]-3-[rac-(4S)-8-chloro-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4- yl]ureal-[rac-(4S)-8-chloro-3,4-dihydro-2H- f X <,■spyrano[3,2-b]pyridin-4-yl]-3-[4-[rac- M X M ■ ( 1 S)- 1 -hydroxyethyl]oxazol-2- ■i, '--Nyl]ureaO O'-^A\ l-[rac-(4S)-8-chloro-3,4-dihydro-2H- OkXpyrano[3,2-b]pyridin-4-yl]-3-[4-[rac- X A 1HH 0( 1 R)- 1 -hydroxyethyl]oxazol-2- yl]urea u1 -[ 1 -(4-cyano-2-fluoro-,,r / 1x. X phenyl)pyrazol-3 -yl] -3 - [rac-(4 S) -8 - chloro-3,4-dihydro-2H-pyrano[3,2- ll 3 'Xx b]pyridin-4-yl]urea9”'l-[2-(3-methyl-lH-pyrazol-5- yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- A / X A / “" XU k’fT 3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea / \ z? Xk xA. / \ i l-[2-(lH-pyrazol-3-yl)thiazol-4-yl]- 3-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]urea1 -[2-( 1 -methyl- 1,2,4-triazol-3 - Iyl)thiazol-4-yl]-3-[rac-(4S)-8-chloro- x; AY XM3,4-dihydro-2H-pyrano [3,2- AYIb]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure<r’1 j ray^ \ 1 - [2 -( 3 -pyridyl)thiazol-4-yl] -3 -[rac- Ok X "4 ) 8 Bf-r x( S 8 A - ' 8 / / -chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]ureal-[2-(4-pyridyl)thiazol-4-yl]-3-[rac- 1 1 I A Zk X (4S)-8-chloro-3,4-dihydro-2H- 'A’""pyrano[3,2-b]pyridin-4-yl]urea xxl-[2-[l-(2,2-difluoroethyl)pyrazol-3- yl]thiazol-4-yl]-3-[rac-(4S)-8-chloro- 3,4-dihydro-2H-pyrano [3,2- 1 1 Ab]pyridin-4-yl]urea uJ1 -[2-( 1 -methylpyrazol-3-yl)thiazol-4- yl]-3-[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea r:\.l-[rac-(4S)-8-chloro-3,4-dihydro-2H- " F pyrano[3,2-b]pyridin-4-yl]-3-[2-[l- (2,2,2-trifluoroethyl)pyrazol-3- I 1 £W"rY yl]thiazol-4-yl]urea / s a X l-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[2-[l-z1. J j i ''A (trideuteriomethyl)pyrazol-3 - yl]thiazol-4-yl]urea V,(S)- 1 -(2-(bicyclo[ 1.1. l]pentan- 1 - yl)thiazol-4-yl)- 3 -(8-chloro-3,4-dihydro-2H- 1 i r v z\ pyrano[3,2-b]pyridin-4-yl)ureaA x ■Attorney Docket No. PTZ-011WOTable 4Chemical Name Structurel-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 -thiazol- 4-yl-urea 1 [ \I '■■■'Ay L AZ M L J1 -[2-( 1 -methylpyrazol-3 -yl)thiazol-4- 1yl]-3-[rac-(4S)-8-(l-methylpyrazol-3- y 1) -3,4-dihydro-2H-pyrano [3,2- b]pyridin-4-yl]urea <1 1,1. I1 J * *(S)-l-(8-ethyl-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(l-phenyl-lH- L XJX )Ypyrazol-3-yl)urea(S)-l-(8-cyclopropyl-3,4-dihydro- 2H-pyrano[3,2- _ \ b]pyridin-4-yl)-3-(l-phenyl-lH- K 1 / pyrazol-3-yl)urea ITtert-butyl (2-(3 -hydroxy oxetan-3- yl)thiazol-4- yl)carbamate x1X!\~ / r~~i >> ~-—o(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -ethyl- 1H-,s. \Z1 'V1 1pyrazol-3-yl)thiazol-4-yl)urea1-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-((R)- 1 -hydroxy- 1 IX / 2-methylpropyl)thiazol-4-yl)ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure1-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-((S)-l-hydroxy- A, A JL / '’'A 2-methylpropyl)thiazol-4-yl)urea \ J / (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-( 1 -isopropyl- 1H- s A. AA pyrazol-3-yl)thiazol-4-yl)urea A, A, A / A i ft ii(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-neopentyl- 1. 12H- 1,2,3 -triazol-4-yl)thiazol-4- yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- C.:b]pyridin-4-yl)-3 -( 1 -(4-cyanopyridin- 1 II r A 2-yl)- lH-pyrazol-3 -yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(tert-pentyl)- 2H- 1,2,3 -triazol-4-yl)thiazol-4-.1.. A AX I yl)urea A Al-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- 1 p? V / \ A b]pyridin-4-yl)-3 -( 1 -(3 -fluoro-4-((S)- 2,2,2-trifluoro-l- VZA_ hydroxyethyl)phenyl) - 1 H-pyrazol-3 - 1 / A yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- Ob]pyridin-4-yl)-3 -( 1 -(3 -fluoro-4-((R)- "i A / k rs.i\ / ?\ / \" K A — 2,2,2-trifluoro-l- hydroxyethyl)phenyl) - 1 H-pyrazol-3 - 1 " ' A'!yl)ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- Ct l h 1 r Y. b]pyridin-4-yl)-3-(2-(2-(2,2,2- ■C-f' Ar k trifluoroethyl)-2H- 1,2,3 -triazol-4-! * *yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2- 0..... Acyclobutylthiazol-4-yl)urea AA A «ZA V >l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- / **■b]pyridin-4-yl)-3-(6-((S)-2,2,2- i A. x ri x. x. x.. trifluoro- 1 -hydroxyethyl)pyridin-2- V yl)ureal-((S)-8-chloro-3,4-dihydro-2H- Jpyrano[3,2- b]pyridin-4-yl)-3-(6-((R)-2,2,2- trifluoro- 1 -hydroxyethyl)pyridin-2- A' ■i’i'yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(6-cyanopyridin- 3 -yl)- lH-pyrazol-3 -yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-isobutylthiazol- 4-yl)urea-X «8(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-( 1 -isopropyl- 1H-. 1 J. A Z'~<\ i ' pyrazol-4-yl)thiazol-4-yl)urea H MAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure(S)-l-(l -(4-(3 -aminooxetan-3 - yl)phenyl)- IHpyrazol- 'f 1 a / S::! S5\ I? f X— ~Z X! i 3 -yl) -3 -(8-chloro-3,4-dihydro-2H- A -V v X f'T" 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- f 'i j n 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- / . Vo / \ 1 1 \ yl) - 1 H-pyrazol-3 -yl)ureaf T / v “l-((S)-8-chloro-3,4-dihydro-2H- \. \ / pyrano[3,2- / b]pyridin-4-yl)-3 -( 1 -(4-fluoro-3 -((R)- nsA / -rv 2,2,2-trifluoro-l-x\ 1 / ■ hydroxyethyl)phenyl) - 1 H-pyrazol-3 - f i - - 1 I'yl)ureal-((S)-8-chloro-3,4-dihydro-2H- f pyrano[3,2- X A p b]p rt iyridin-4-yl)-3 -( 1 -(4-fluoro-3 -((R)- 2,2,2-trifluoro-l- f i 1hydroxyethy z'v X'" A. / X -Vl)phenyl) - 1 H-pyrazol-3 - 1 yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(3 - methylpyridin-2-yl)- lH-pyrazol-3 - yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- t’ pyrano[3,2-<-1'^.. As-' A'. X51>- Xb]pyridin-4-yl)-3 -( 1 -(5 -cyanopyridin- 'y '"3" T ” ” 'w2-yl)- lH-pyrazol-3 -yl)ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-isopropylthiazol- i 3.14-yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- "'"'Vb]pyridin-4-yl)-3 -( 1 -(4-((R)- 1 - hydroxy ethyl)phenyl) - 1 H-pyrazol-3 - / yl)urea / \l-((S > <. \ £)-8-chloro-3,4-dihydro-2H- pyrano[3,2- \ / b]pyridin-4-yl)-3 -( l-(4-((S)-l- I x-'’ A ''a / % A X — / \ 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 - 1 1 X'\hydroxy cyclobutyl)- lH-pyrazol-4- A A A / \ I yl)thiazol-4-yl)urea(S)-4-(4-(3-(8-chloro-3,4-dihydro- 2Hpyrano[ A J3,2-b]pyridin-4-yl)ureido)thiazol-2- ' X - A A- / yl)-N-methylbenzamide V(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(4- X ■y X y X Y X2 * A >—-»■ cyanophenyl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- X pyrano[3,2- b]pyridin-4-yl)-3 -( 1 -(4-cyano-2- 1 \v's. J Amethylphenyl) - 1 H-pyrazol-3 -yl)urea y ■<< * * _l-((S)-8-chloro-3,4-dihydro-2H- 3 '•> rs®«\pyrano[3,2- <3 Xb]pyridin-4-yl)-3 -( 1 -(6-((R)-2,2,2- y --„ V X T XxM / \ W\ — ( \ trifluoro- 1 -hydroxyethyl)pyridin-3 - yl)- lH-pyrazol-3 -yl)urea A"Attorney Docket No. PTZ-011WOTable 4Chemical Name Structurel-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- I:: J > / \ / b]pyridin-4-yl)-3-(l-(6-((S)-2,2,2- •■■■Ktrifluoro- 1 -hydroxy ethyl)pyridin-3 - if " Y -A. Yr tr * \ yl)- lH-pyrazol-3 -yl)urea I J f / A s l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-. _ _ / . b]pyridin-4-yl)-3 -( 1 -(6-((S)-2,2,2- 1 1 11 r::\ \ x-Ax A 1 A > —trifluoro- 1 -hydroxyethyl)pyridin-3 - f ""ft' X X '■xx -' ifyl)- lH-pyrazol-3 -yl)ureav-.l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- X-.. V. / b]pyridin-4-yl)-3-(l-(3-((R)-2,2,2- • | ■' \ y trifluoro- 1 -hydroxyethyl)phenyl)- 1H- pyrazol-3-yl)urea VsA vVA > (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(5 - methylisoxazol-4-yl)thiazol-4-yl)ureaCi. i •A i 1 i i r\ < K ((J(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-(methyl-d3)- 2H- 1,2,3 -triazol-4-yl)thiazol-4-... H 1 | I H 1 H.1 "f yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- A. x'S.., Ax --A / \\ A--—-' b]pyridin-4-yl)-3 -( 1 -(4- xNX 4Z(methoxymethyl)phenyl)- 1H- pyrazol-3-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -( 1 '-methyl- 1 'H- f Y i FY -O— [ 1,4'-bipyrazol] -3 -yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- t 1 B & \ Oi-S i i I 1 A™- A b]pyridin-4-yl)-3-(2-(4-((R)-2,2,2- X'x ». / -4 \ -—x- / / V-Z > trifluoro-1- / \Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure hydroxyethyl)phenyl)thiazol-4- yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- i i r / ’is b]pyridin-4-yl)-3-(2-(4-((S)-2,2,2- X f V T \ trifluoro-1-! / ?■■= hydroxyethyl)phenyl)thiazol-4- yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- B r\ / -^ b]pyridin-4-yl)-3 -( 1 -(4-(2- A A.. hydroxyethyl)phenyl) - 1 H-pyrazol-3 - Ayl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-(2-(3,3 - A ■> A”\.-?-k difluorocyclobutyl) -2H- 1,2,3 -triazol- A j, 1 T4-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- o'"' A tb]pyridin-4-yl)-3 -( 1 '-methyl- 1 'H- X, s' X k;-„ J-, J \ A / \ s [ 1,4'-bipyrazol] -3 -yl)ureaA J(S)-l-(l -(3 -bromophenyl) - 1 H- pyrazol-3-yl)-3-(8- f'* \ / ..-... A / chloro-3,4-dihydro-2H-pyrano[3,2- ek, J. A. Jb]pyridin-4-yl)urea A-" Y \ N xA, ■’ / % & / XZ(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -( 1 -methyl -2- i I roxo- 1,2-dihydropyridin-4-yl)- 1H- pyrazol-4-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- st » \ / b]pyridin-4-yl)-3 -(2-(pyridin-2- yl)thiazol-4-yl)urea j"'*' AZAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- iib]pyridin-4-yl)-3 -(2-( 1 -methyl- 1H- Ax A / \ 1'Npyrazol-3-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- k A zA. / Y. Ay b]pyridin-4-yl)-3 -( 1 -(4-(2- hydroxypropan-2-yl)phenyl)- 1H- pyrazol-3-yl)ureal-((S)-8-chloro-3,4-dihydro-2H- r ■ \. / Y x pyrano[3,2-.11 1 b]pyridin-4-yl)-3 -( 1 -(4-((R)- 1, 1, 1 - Y Ivtrifluoro-2-hydroxypropan-2- yl)phenyl)- lH-pyrazol-3 -yl)urea,l-((S)-8-chloro-3,4-dihydro-2H- 1 » fsss\ A X J J.-■•-. A / pyrano[3,2- X3 A Yr "■a A / \ b]pyridin-4-yl)-3 -( 1 -(4-((S)- 1, 1, 1 - trifluoro-2-hydroxypropan-2- yl)phenyl)- lH-pyrazol-3 -yl)urea(S)-4-(4-(3-(8-chloro-3,4-dihydro- 2Hpyrano[ 1 / ■ — (, \ _ / 1. A3,2-b]pyridin-4-yl)ureido)thiazol-2- yl)benzamide(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(6-( 1 -cyclobutyl - lH-pyrazol-4-yl)pyri din-2 -yl)urea k(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -cyclopropyl - 1 J. IL 1 z> X 'X 'X.-' X X '■■N lH-imidazol-4-yl)thiazol-4-yl)urea M iiN(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- > <.-■■■■ \,>-x xY: « \ / / '~X b]pyridin-4-yl)-3 -(2-( 1 - x '1 ' 'x. (difluoromethyl)- lH-pyrazol-4- -"-iX ''M \ssss4 yl)thiazol-4-yl)ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure((S)-l-(l-(4-cyanophenyl)-lH- pyrazol-3-yl)-3-(8-, r \ z™zjj kmethyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea;i / — < V / 1 ”. J((R)- 1 -( 1 -(4-cyanophenyl)- 1H- pyrazol-3-yl)-3- ( 8 -methyl -3,4-dihydro -2H-. (. ). pyrano[3,2-b]pyridin-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- 'i o.--" X «... b]pyridin-4-yl)-3-(2-(2-(2- i H Z Ax cya r n Jy 4 Kno p "'X Z ' Xo vX f " A p a -2-yl)-2H- 1,2,3 -triazol- fi H4-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- 1 J 1 / — { (methylamino)phenyl)thiazol-4- yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- _ / b]pyridin-4-yl)-3 -(2-(3 -fluoro-4- hydroxyphenyl)thiazol-4-yl)urea ] i f J.4 ).l-((S)-8-chloro-3,4-dihydro-2H- s. pyrano[3,2- b]pyridin-4-yl)-3-(2-((S)- " A I. 1 jl z:a. < I tetrahydrofuran-3 -yl)thiazol-4- yl)urea 0l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- I jTyxi b]pyridin-4-yl)-3 -(2-((R)- tetrahydrofuran-3 -yl)thiazol-4-C!\ X HZ '■'* v-""' yl)urea aX.Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure(R) - 1 -( 1 -(4-cyanophenyl) - 1 H- pyrazol-3-yl)-3- (3,4-dihydro-2H-pyrano[3,2- X X,1 xxrx. b]pyridin-4-yl)urea X "w*(S)-l-(l -(4-cyanophenyl) - 1 H- pyrazol-3-yl)-3- (3,4-dihydro-2H-pyr ✓A X 1 X i A B i. A!’A / X — d \ AA ano[3,2- / / \ b]pyridin-4-yl)urear~~- (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-( 1 -isopropyl- 1H- j-. Ji / \ J X pyrazol-4-yl)thiazol-4-yl)ureax* X (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(2- A A / \ ■ cyanopropan-2-yl) - 1 H-pyrazol-3 - f “ayl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- V pyrano[3,2- T 1 I f XjX'X <3„ Yx, A yA. / f \ 1 '<flb]pyridin-4-yl)-3 -(2-( 1 -(2- cyanopropan-2-yl)- lH-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 -cyclopropyl - X x X X A / 'r ''f' lH-pyrazol-4-yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- X 1! A''\I J!' b]pyridin-4-yl)-3 -(2-( 1 -cyclopropyl - lH-pyrazol-4-yl)thiazol-4-yl)urea 'IXAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure( S)- 1 -( 8 -chloro -3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(6-cyanopyridin-2- yl)ureal-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3-(2-( 1 -(( ls,3R)-3- 1? hydroxy cyclobutyl) - 1 H-pyrazol-3 - yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- zpyrano[3,2- M / „b]pyridin-4-yl)-3 -(4-(4- ■*' A Mv' 1 J.V.'*: T A A MM * / / cyanophenyl)oxazol-2-yl)urea \ / _1 -(2-((S)- 1 -hydroxyethyl)thiazol-4- yl)-3-((S)-8- I J 1 u! A I! \ \.p methyl-3,4-dihydro-2H -yu -pyrano[3,2- b]pyridin-4-yl)urea h' XX Y X _\ X A \ \ / 1 -(2-((S)- 1 -hydroxyethyl)thiazol-4- yl)-3-((R)-8- \ / — methyl-3,4-dihydro-2H-pyrano[3,2- / b]pyridin-4-yl)urea x. j 1 1 rxz X" (S)-4-(3-(3-(8-chloro-3,4-dihydro- 2Hpyrano[ i:; \ \1 — -A \ / 3,2-b]pyridin-4-yl)ureido)-lH- MX ■A / ■-< pyrazol- 1 -yl)-2-fluoro-N- “ ■4 methylbenzamide XT(S)-4-(4-(3-(8-chloro-3,4-dihydro- / • / 2Hpyrano[3,2-b]pyridin-4-yl)ureido)thiazol-2- A"- yl)-2-fluoro-N-methylbenzamide V / ~\Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- A 0b]pyridin-4-yl)-3 -(2-( 1 -( 1 -methoxy- X. / \! i 2-methylpropan-2-yl)-lH-pyrazol-4- X,'lX- 1 x 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- L H 7' pyrazol-3-yl)thiazol-4-yl)urea 1 1 J(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 8 >•(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- ■ r v / b]pyridin-4-yl)-3 -(2-(2- methyloxazol-5-yl)thiazol-4-yl)urea 8((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2- O r'\ y X / ' 'i —... / b]pyridin-4-yl)-3 -(2-(4-((S)- 1 - 8 hydroxyethyl)phenyl)thiazol-4- yl)urea I. ^.1((S)-8-chloro-3,4-dihydro-2H- X.pyrano[3,2- j r; A 2 _ / \ / OH b]pyridin-4-yl)-3 -(2-(4-((R)- 1 - if hydroxyethyl)phenyl)thiazol-4- 1yl)urea X,(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(3,3 - O r\ difluorocyclobutyl) - 1 H-pyrazol-3 - j yl)thiazol-4-yl)urea1Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure(S)-6-(3-(8 -chloro-3,4-dihydro-2H- pyrano[3,2- ■A yb]pyridin-4-yl)ureido)picolinamide / \ - s « H ii / / K A'\. \\ / X / si \4-[3-[[(4S)-8-chloro-3,4-dihydro-2H- / pyrano[3,2- A i r\p rdn A A xb] yi i -4-. AX A- / T r «' A. A yl] carbamoylamino]pyrazol- 1 -yl] -N- w \ (2-hydroxyethyl)benzamide(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(6-( 1 -(oxetan-3 -yl)- '' A'A " V AA AA X. / ^X} lH-pyrazol-4-yl)pyridin-2-yl)urea 1 1. / A (R)-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 “I XX-Xz* 1 -(2-((R)-l-hydroxyethyl)thiazol-4- yl)-3-((R)-8- 1 jj r\ methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea X A \1 -(2-((R)-l-hydroxyethyl)thiazol-4- yl)-3-((S)-8- methyl-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)urea X 1 1 X JL AXA1 -[2-(4-hydro j x ' Ax, A i A r, A>. x w x / / . - xyphenyl)thiazol-4-yl] - 3-[rac-(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structureo1 -[2-(4-hydroxyphenyl)thiazol-4-yl] - p V J ry-n >- 3-[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-.... n b]pyridin-4-yl)-3 -(2-( 1 -cyclobutyl - CilH-pyrazol-4-yl)thiazol-4-yl)urea Al(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- X.. L f. / b]pyridin-4-yl)-3 -(2-( 1 -cyclobutyl - J 1,,-C / \ lH-pyrazol-4-yl)thiazol-4-yl)urea H ftl-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-.......,xb]pyridin-4-yl)-3 -(2-( 1 -(( 1 s,3 S)-3 - A.. Ahydroxy cyclobutyl)- lH-pyrazol-4- 1 yl)thiazol-4-yl)urea •<l-((R)-8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(( 1 s,3 S)-3 - hydroxy cyclobutyl)- lH-pyrazol-4- A A A? —ft ft ( i yl)thiazol-4-yl)urea(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- A -X. I b]pyridin-4-yl)-3 -(2-(3,5 - dimethylisoxazol-4-yl)thiazol-4- v'* A A '" M' AA / 'I yl)ureaH / 4-[3-[[rac-(4S)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b]pyridin-4- X J... A A / ( — / yl]carbamoylamino]pyrazol- 1 -! ”yl]benzamide4-[3-[[rac-(4R)-8-chloro-3,4-dihydro- 1 |! r w~"\ / 2H-pyrano [3,2-b]pyridin-4- yl]carbamoylamino]pyrazol- 1 - V / ~Ayl]benzamideAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure( S)- 1 -( 8 -chloro -3,4-dihydro-2H- pyrano[3,2- r"b]pyridin-4-yl)-3 -(2-( 1 -(2- X J. 1 x / -A 7' hydroxyethyl)- lH-pyrazol-4- 7.^yl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(2- s. if 1"” Ahydroxy ethyl)- 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 -(2,2,2- A 1 X A > AA"'A< trifluoroethyl)- lH-pyrazol-4- yl)thiazol-4-yl)urea I JY" ' (R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)-3 -(2-( 1 -(2,2,2- X' 1 1 £kkrk<- trifluoroethyl)- lH-pyrazol-4- yl)thiazol-4-yl)urea J(R)- 1 -(2-acetylthiazol-4-yl)-3-(8- methyl-3,4- dihydro-2H-pyrano[3,2-b]pyridin-4- yl)urea t ] -15 J If r ■»v \\ z-A(R)- 1 -(2-acetylthiazol-4-yl)-3-(8- methyl-3,4- '"'Adihydro-2H-pyrano[3,2-b]pyridin-4- j 1 1 i ky yl)urea \ X - x(R)- 1 -(8-methyl-3,4-dihydro-2H- rx!<= / i pyrano[3,2- b]pyridin-4-yl)-3-(2-(l-(oxetan-3-yl)- g J!flH-pyrazol-4-yl)thiazol-4-yl)ureaAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure(R)- 1 -(8-methyl-3,4-dihydro-2H- / A" pyrano[3,2- X 3 b]pyridin-4-yl)-3-(2-(l-(oxetan-3-yl)- X,lH-pyrazol-4-yl)thiazol-4-yl)urea A A / rXT / U(S)-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)ureazf. "''W / 7y _ \ fi il ■' "(R)-l-(8-chloro-3,4-dihydro-2H- \ / - pyrano[3,2- b]pyridin-4-yl)-3-(2-(2-methyl-2H- jL JL X A F l,2,3-triazol-4-yl)thiazol-4-yl)urea A X -A A»55” A(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- A, A, / A i 1 4-yl)-3-(2-(l-(2,2-difluoroethyl)-lH- pyrazol-4-yl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-(l-(2,2-difluoroethyl)-lH- pyrazol-4-yl)thiazol-4-yl)urea1 -(6-(4-(2-aminopropan-2- yl)phenyl)pyridin-2-yl)-3 - 11X1^ (8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea! “ I A, (S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- j 1 h II > — X A,. A. A. / x Ci X 4-yl)-3-(2-( 1 -(2 -methoxyethyl)- 1H- • <4 Hpyrazol-4-yl)thiazol-4-yl)urea(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- A A A. / ~A T ' 4-yl)-3-(2-( 1 -(2 -methoxyethyl)- 1H- Hpyrazol-4-yl)thiazol-4-yl)ureaAttorney Docket No. PTZ-011WO / / Table 4IChemical Name Structure >o (S)-l-(8-chloro-3,4-dihydro-2H- / % pyrano[3,2-b]pyridin- I4-yl)-3-(2-(l-ethyl-lH-pyrazol-4- yl)thiazol-4-yl)ureaR / % X X J u( )-l-(8-chloro-3,4-dihydro-2H- / pyrano[3,2-b]pyridin- 4-yl)-3-(2-(l-ethyl-lH-pyrazol-4- I.1 \.1 s X >■£" yl)thiazol-4-yl X \ r )ureaA / "(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- / 4-yl)-3-(2-cyclopropylthiazol-4- Ck,yl)ureaT(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- \. 4-yl)-3-(2-cyclopropylthiazol-4- f X.1.£ > <i yl)urea M i-i V I ZX" '"'-'-x (R)-4-(3 -(3 -(8-chloro-3,4-dihydro- 2H-pyrano[3,2- t i lb]pyridin-4-yl)ureido)- IH-pyrazol- 1 - A yl)-N-((3 -methyloxetan-3 - yl)methyl)benzamide(S)-4-(3-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2- b]pyridin-4-yl)ureido)- IH-pyrazol- 1 - yl)-N-((3 -methyloxetan-3 - yl)methyl)benzamidel-((R)-8-chloro-3,4-dihydro-2H- C> X PH pyrano[3,2-b]pyridin- 4-yl)-3-(2-((S)-l- k X f-i \ hydroxyethyl)thiazol-4-yl)ureaVAttorney Docket No. PTZ-011WOTable 4Chemical Name Structurel-((R)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-((R)-l- hydroxyethyl)thiazol-4-yl)urea,l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-((S)-l- hydroxyethyl)thiazol-4-yl)urea,l-((S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-((R)-l- hydroxyethyl)thiazol-4-yl)urea,(R)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- 4-yl)-3-(2-(l-(3,3- It \ difluorocyclobutyl)- lH-pyrazol-4- yl)thiazol-4-yl)urea i j ”((S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2- rA b]pyridin-4-yl)-3 -(2-( 1 -(3,3 - difluorocyclobutyl)- lH-pyrazol-4- I •4 £> X'X yl)thiazol-4-yl)urea(R)-6-(3-(8-methyl-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide,XX J^L I Jr ¥r (S)-6-(3-(8-methyl-3,4-dihydro-2H- pyrano[3,2- b]pyridin-4-yl)ureido)picolinamide a i -.j J. J. £ iAttorney Docket No. PTZ-011WOTable 4Chemical Name Structurel-[rac-(4S)-8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl]-3-[l-[4- [rac-( 1 R)-2,2,2-trifluoro- 1 -hydroxy- ethyl]phenyl]pyrazol-3-yl]ureal-[rac-(4R)-8-chloro-3,4-dihydro- cY1 g2H-pyrano [3,2-b] pyridin-4-yl] -3 - [ 1 - s..[4-[rac-( 1 R)-2,2,2-trifluoro- 1 - 4 Tvhydroxy-ethyl]phenyl]pyrazol-3 - yl]urea(R)- 1 -(2-(4-(2-aminopropan-2- yl)phenyl)thiazol-4- / \yl)-3-(8-chloro-3,4-dihydro-2H- v Y * ^4 V, pyrano[3,2-b]pyridin-4-yl)urea(S)- 1 -(2-(4-(2-aminopropan-2- A " syl)phenyl)thiazol-4- £1 1yl)-3-(8-chloro-3,4-dihydro-2H- | » * - W: pyrano[3,2-b]pyridin-4-yl)urea kl-(8-chloro-3,4-dihydro-2H- bpyrano[3,2-b]pyridin-4- J£ Iyl)-3-(2-(2-methyl-2H-l,2,3-triazol- 44.,■'•4.. 4 ft 1 \ I 4-yl)thiazol-4-yl)ureaI8 8(S)-4-(4-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2- X X J.. JL 4-4 > Y b]pyridin-4-yl)ureido)thiazol-2-yl)- N -((3 -methyloxetan-3 - yl)methyl)benzamide(R)-4-(4-(3-(8-chloro-3,4-dihydro- 2H-pyrano[3,2- 1 I 1 < \ / b]pyridin-4-yl)ureido)thiazol-2-yl)- N -((3 -methyloxetan-3 - yl)methyl)benzamide '" J.4-(4-(3 -(8-chloro-3,4-dihydro-2H- f pyrano[3,2- £ fi / ^< ik Pb]pyridin-4-yl)ureido)thiazol-2-yl)-2- II — ( \ / 'ff"!f ’fi'x _ \\ fluoro-N-methylbenzamideAttorney Docket No. PTZ-011WOTable 4Chemical Name Structurex X Oz\ / .^ r\Hi I — z X l-[(4S)-8-chloro-3,4-d X-y X--.-. "n'' A As « / 'X \\ / / ihydro-2H- pyrano[3,2-b]pyridin-4-yl] -3 -[ 1 -(4- r \. cyanopheny ’Yl)pyrazol -3 -yl]ureaCk x l-[(4R)-8-chloro-3,4-dihydro-2H- •NY'' >{’ N X pyrano[3,2-b]pyridin-4-yl] -3 -[ 1 -(4- cyanophenyl)pyrazol -3 -yl]ureal-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4- 1 1 £>¥ yl)-3-(2-(2-hydroxypropan-2- X X" A z- yl)thiazol-4-yl)urea(R)- 1 -(6-(4-(3 -aminooxetan-3 - yl)phenyl)pyridin-2- Ci *” yl)-3-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin-4-yl)urea(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 / Yl-[rac-(4S)-8-chloro-3,4-dihydro-2H- £Y. i rvo / • pyrano[3,2-b]pyridin-4-yl]-3-[l-[4- 1 T V T' V Z~X [rac-( 1 S)-2,2,2-trifluoro- 1 -hydroxy- ~ X f-' ethyl]phenyl]pyrazol-3-yl]ureal-[rac-(4R)-8-chloro-3,4-dihydro- 2H-pyrano [3,2-b] pyridin-4-yl] -3 - [ 1 - A A A Y X [4-[rac-( 1 S)-2,2,2-trifluoro- 1 - hydroxy-ethyl]phenyl]pyrazol-3 - yl]ureaAttorney Docket No. PTZ-011WOTable 4 „, i S ' Che ica Nam Str ctu e 1 v m l e u r(R)-l-(8-chloro-3,4-dihydro-2H- kA pyrano[3,2-b]pyridin- i 0 Ax X f 4-yl) -3 -(2-( 1 -(oxetan- "l 3 -yl) - 1 H- --JC5Xpyrazo -4- l)thiazol-4-yl)urea n, 1 Xl y I( "Q(S)-l-(8-chloro-3,4-dihydro-2H- pyrano[3,2-b]pyridin- / / V 1 8. J 'i, ft' \.x ""4 4-yl) -3 -(2-( 1 -(oxetan-3 -yl) - 1 H-.. i A. A r pyrazol-4-yl)thiazol-4-yl)u $; / \ / \. B Bl-(2-acetylthiazol-4-yl)-3-(8-chloro- y. z $ X3,4-dihydro-2Hpyrano [ A 'I Ji r" \ / 3,2-b]pyridin-4-yl)urea axX X - '(" V AZ \ Av Xl-(3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2- ((R)-3 -hydroxypyrrolidin- 1 - yl)thiazol-4-yl)ureal-(3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl)-3-(2- ((R)-3 -hydroxypyrrolidin- 1 - '"'J.cv £> -<") yl)thiazol-4-yl)urea ||J "1 -[ 1 -[4-( 1 -amino- 1 -methyl - ethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8- chloro-3,4-dihydro-2H-pyrano[3,2- b]pyridin-4-yl]urea1 -[ 1 -[4-( 1 -amino- 1 -methyl - ethyl)phenyl]pyrazol-3-yl]-3-[(4R)-8- C:xrvz A / / . ~\ / ^ chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]ureaAttorney Docket No. PTZ-011WOAttorney Docket No. PTZ-011WOTable 4Chemical Name Structure! I § \ £""-^ J... A x / — \ i / V VV%AJ'O Jxp-'X 0r-'-\! / \ / X" \ x x A x. Z~x i" X / \ £ r%~ / \ / / \ » / \S _. A* & tz\a. k 1 1Y y Y "£■rjSsrs\ x- J Ji £X '"% HxX HX’xA \Xar i. ^ ta?L £_r"\.., AA.C,'-x. zXv X 2X / \1Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure% A \ / (v.!‘ X. 1 J. A 'L \ / \ > XvA' '■■A'- ~V z™ \ At / "H\ \ Z-A'*<> BV / \I 3 r\ \'1 0 Z"~“f 4. JI A 9—.. " Vxif \=s« / z"\z'"^ > 'X O X'"’ \ J. 1 X. JL / \ A X"'' f~~\Av. / v / £YXs'' s$ \ [ i * B P / > L t-,.■■■'*■' A''' cuxx / ’’A'" ' 'N '^ '"'A r y s-s H, XG''* 1 y p ilcu A"%x‘X-'" 'A*' "i Si H |. / T JV™ i-Attorney Docket No. PTZ-011WO £ - Table 4kx" Chemical Name Structure j f)v§ h.1 \ Z 1 4., 1 I iV'~Z '’Si*'" '" N \ M H / v.»*MX / / "? 1 <c^ f?r;:' 'i U '! C!.^ ', X., / \ j Nf" ■"'%*'■' '''H’"' ''’« V— - - - | l_ / \y y X\ / \x / / '"i0 / / / 'J j [| [ ]CK A X", ZZ Z=< / \ / '■'if ■'■'f' 'N' 'N** - "'f - F 1 " " \ NFcZ Z O1 II f \ z -K Z>xZ Zx / \ Z\‘ZZNXZZ \ / N- IJ "HC*x Z * ■•' -A. AM, Z**^ \ "’"^t:::::::^ i H HIj r \^ / '\''a-'’ '■« \zH iiM ^ir’ Xx'sr A w / A '). kA — X / / / \ -Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure1 H r^yx A H A X H Az‘ZJ A ■*<• Z / / ■*> \r 1 | r^'\x 1 1 o M. y- y X T '* \£ / \ / , _€< s, x. J,, A A / '"'-z i: Xj H.y'* A-O 'Xi' \ '*. A X. ^<0£S<I 1 \ / r"" Z;<z:;>A. y"' X, ‘yzAS‘'xj’'' A. A< A \<*$£• J:',‘^ 1 * “V, J<"Xt 1 li f \ A''- AC-v, £? | $ ifzAzN / OZ'" AZ Ws?* •*.>1 I \ ^A / v\^zW?.,v11 1 i £> A. ) pxXx z-'v^ x '■«■ \< -y U " ’X §A" X, ri i,o-o§: K '<<Avyz zz<^Attorney Docket No. PTZ-011WO Table 4Chemical Name Structure1! I 1 J rA Az / ~~x _ / J I A Z / s \> < r. / \' iIiX<<1 A A / I O Z rAl.[ >~ / "r A,Attorney Docket No. PTZ-011WOTable 4Chemical Name Structure£1 1 £ > < u1 r\I i i f v

[0093] 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.Attorney Docket No. PTZ-011WO

[0094] In some embodiments, the compound of formula (V) is a compound listed in Table 5.u.It 1 Table 5Chemical Name Structure J z1 - [ 1 - [4 -( 1 -hy droxy- £1-methyl- i v h Y\ N< — ZA \ / 0Hethyl)phenyl]pyrazo x. 'A / A — - " N ’N y % / \ l-3-yl]-3-[rac-(lS)- 1- V V H H ' cy cl opropy 1 ethyl ]urea / Ll-[2-[l-(l-cyano-l- methyl- = JF-S V ethyl)imidazol-4-: 0 V _ / / Nyl]thiazol-4-yl]-3- j zx < A A ■ \! N [rac-(lS)-l- " NN. ■V ill h f **■'cy cl opropy 1 ethyl ]urHeal-[2-(l,5- dimethylpyrazol-3- H N yl)thiazol-4-yl]-3- t[rac-(lS)-l- " " N Wkcy cl opropy 1 ethyl ]ur H \ ea VHE Fl-[rac-(lS)-l- cy cl opropy 1 ethyl ] - \ A / -F3-[l-[2- (trifluoromethyl)-4- pyridyl]pyrazol-3 - yl]urea r V-Z A N JL N N \H Hl-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[5- (trifluoromethyl)-3 - pyridyl]pyrazol-3 - yl]ureaAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurel-[rac-(lS)-l-F\ F cy cl opropy 1 ethyl ] - y_ 3-[l-[6- (t / Frifluoromethyl)-2-? Jpyridyl]pyrazol-3 - yl]urea N\ / H HF Fl-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[4- UF(trifluoromethyl)-2- pyridyl]pyrazol-3 - yl]urea V A A X > XV~Z N NT N )H HNl-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[2-[l -(2,2,2- s O rr-A N- xF trifluoroethyl)pyraz v™ z"' X 'N JL 'N" X N C F ol-3-yl]thi V H H *azol-4- yl]ureal-[2-(l- cyclopropylimidazo= ol-4-yl)thiazol-4-yl]- 3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ur X A X A " eal-[rac-(lS)-l- V n ae"F Fcy cl opropy 1 ethyl ] - 3-[2-[4-[rac-(lR)- 2,2,2-trifluoro-l- hydroxy- V H H 'N' _ / \ OH ethy 1 ] phenyl ] thi azol-4-yl]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[2-[4-[rac-(lS)-5? A3'- 2,2,2-trifluoro-l- hydroxy- \ / ,4. H A H 1 / '~~i X-*-!-7OH ethy 1 ] phenyl ] thi azol-4-yl]ureaAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurel-[l-[3-fluoro-4- [rac-(lR)-2,2,2- / F F\ F tri fluoro- 1 -hydroxy - ethyl]phenyl]pyrazol-3-yl]-3-[rac-(lS)- 1- V H H OH cy cl opropy 1 ethyl ]ureal-[l-[3-fluoro-4- [rac-(lS)-2,2,2- / *\ / Fi o r=A / =< KF tri fluoro- 1 -hydroxy- ethyl]phenyl]pyrazo "bT '~N'X" X _ / \l-3-yl]-3-[rac-(lS)- V H H OH1- cy cl opropy 1 ethyl ]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - HOJ f 3-[l-[3-[rac-(lR)- A — F—F 2,2,2-trifluoro-l- hydroxy-1 -methyli itN—?ethyl ] pheny 1 ]py razo v — N NT N y _ _l-3-yl]urea \ / H Hl-[rac-(lS)-l- HO., Icy cl opropy 1 ethyl ] - 3-[l-[3-[rac-(lS)- 2,2,2-trifluoro-l- hydroxy-1 -methyl1 1 * ethyl ] pheny 1 ]py razol-3-yl]urea V H H1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[2-(l- 1 J 1 T methylpyrazol-3- V-< 'N " N" 'Nyl)thiazol-4-yl]urea V H HAttorney Docket No. PTZ-011WOTable 5Chemical Name StructureHO r l-[rac-(lS)-l- \ / cy cl opropy 1 ethyl ] - 3-[l-[3-[rac-(lR)- 2,2,2-trifluoro-l- hydroxy- I 1Fe v-7^ \ IT N' N A / thy 1 ] pheny 1 ]py razo \ / H H ) — l-3-yl]urea / 1-((S)-1- HOF^O=cyclopropylethyl)- X _ Z_F XX 3-(l-(3-((R)-2,2,2- tri fluoro- 1- hydroxyethyl)phenyE 0 XFl)-lH-pyrazol-3- yl)urea V H Hl-[rac-(lS)-l- L x cy cl opropy 1 ethyl ] - XNo / -.3-[l-[3-[rac-(lS)- S' 2,2,2-trifluoro-l- hydroxy- f■'x"-.R-n ethy 1 ]pheny 1 ] py razo •n l-3-yl]urea1-((S)-1- HOFcyclopropylethyl)- _ Z-F 3-(l-(3-((S)-2,2,2- tri fluoro- 1- hydroxyethyl)pheny? 0 X|Zl)-lH-pyrazol-3- yl)urea V H Hl-[rac-(lS)-l- F F cy cl opropy 1 ethyl ] - 3-[2-[4- A A A X — \\ A-o7(trifluoromethoxy)p " K N' -N vyV H H henyl]thiazol-4- yl]ureaAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurel-[2-(l- bicyclo[l.l.l]penta 0nyl)thiazol-4-yl]-3- [rac-(lS)-l- X A 1cy cl opropy 1 ethyl ]ur \ / Li Liea \z ri nl-[l-[4- (methoxymethyl)ph i? rx / ^\ o-— eny 1] py razol -3 -y 1 ] - i 1 x x-A yy3-[rac-(lS)-l- N' " N' 'N V / V H Hcy cl opropy 1 ethyl ]ureal-[l-[4-(2- hydroxyethyl)pheny I t AV ZX / ~"~OH l]pyrazol-3-yl]-3- [rac-(lS)-l- \ / H Hcy cl opropy 1 ethyl ]urea1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-[4-[(lR)-l- v / A lNN / / \ hydroxyethyl]pheny V H Hx1 ] py razol -3 -y 1 ]urea V1-[(1S)-1- cy cl opropy 1 ethyl ] - I 9ZOH 3-[l-[4-[(lS)-l- i JJ L > / hydroxyethyl]phenyV7 / XN'A‘N / \_Z A V H H1 ] py razol -3 -y 1 ]ureaxl-[rac-(lR)-l- cy cl opropy 1 ethyl ] - i 9 rx OH 3-[l-[4-[rac-(lS)- I N Ahr A 'N / NA / / \ 2,2,2-trifluoro-l- hydroxy- VH H / -F ethy 1 ] pheny 1 ] py razo F F l-3-yl]ureal-[rac-(lR)-l- cy cl opropy 1 ethyl ] - I I,o. o x3-[l-[4-[rac-(lR)- V—Z- 'N' 'N'" " N A _ / \ 2,2,2-trifluoro-l- v H Hhydroxy-F FAttorney Docket No. PTZ-011WOTable 5Chemical Name Structureethyl ] pheny 1 ]py razol-3-yl]ureal-[rac-(lS)-l- R F cy cl opropy 1 ethyl ] - 3-[l-[4-[rac-(lR)- 2,2,2-trifluoro-l- JI JLNC J— V hydroxy-1 -methylA / T rreN wr° thyl ] pheny 1 ]py razoHl-3-yl]ureal-[rac-(lS)-l- / zzcy cl opropy 1 ethyl ] - 3-[l-[4-[rac-(lS)- - / / V2,2,2-trifluoro-l- ' zhydroxy-1 -methylethyl ] pheny 1 ]py razol-3-yl]ureal-[rac-(lS)-l- 6cy cl opropy 1 ethyl ] - » IIZOH 3-[l-[6-[rac-(lR)- i jl (\ V— * / 2,2,2-trifluoro-l- V Vy — A H H ■ y-F hydroxy-ethyl]-3- pyridyl]pyrazol-3 - F Y Ox F X I " H yl]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - * II r\ PH 3-[l-[6-[rac-(lS)- A A Xz A / W2,2,2-trifluoro-l- V H H ■hydroxy-ethyl]-3- V~-F pyridyl]pyrazol-3 - F F yl]urea* ol-[rac-(lS)-l- cy cl opropy 1 ethyl ] - J J JL JL3-[6-[rac-(3S)-3- hydroxypyrrolidin- V H H1 -yl]-2-pyridyl]ureabHAttorney Docket No. PTZ-011WOTable 5Chemical Name Structureu LL.0 CL! S11u X!1l-[rac-(lS)-l- fcy cl opropy 1 ethyl ] - Xv3-[6-[rac-(3R)-3- •rA '"''NzNd o y y r l f I 1 hy r x p r o idin- VH HJ X1 -yl]-2-pyridyl]urea! 1A OH / / Hl-(6-pyrrolidin-l- \yl-2-pyridyl)-3-[rac- / ZI(1S)-1- icy cl opropy 1 ethyl ]ur V-X \ \0=I L J2d ' Xea V / H H N 1 / 1-[(1S)-1- \OK / cy cl opropy 1 ethyl ] - t>x3-[l-[4-[(lR)-l- X 1 A 0 1 Z N — ■ / A / \) — Vz'Xx Omethylsulfonylethyl N N N V_ / \ ]phenyl]pyrazol-3- V H Hyl]urea1-[(1S)-1- n / cy cl opropy 1 ethyl ] - 3-[l-[4-[(lS)-l- A Xx methylsulfonylethyl0]phenyl]pyrazol-3- YA U H * \yl]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[4-[rac-(lR)- 2,2,2-trifluoro-l- hydroxy- ethy 1 ] pheny 1 ]py razol-3-yl]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[4-[rac-(lS)- 2,2,2-trifluoro-l- hydroxy-Attorney Docket No. PTZ-011WOTable 5Chemical Name Structureethyl ] pheny 1 ]py razol-3-yl]urea1-[(1S)-1- cy cl opropy 1 ethyl ] - / !X3-[l-[4- (ethylsulfonylmethy A "l)phenyl]pyrazol-3- yl]urea / / 25l-[l-(3- W T25o / bromophenyl)pyraz \ Mol-3-yl]-3-[rac-(l S)- \ / _1- JT\ iiMirmjiMM WKcy cl opropy 1 ethyl ]ur &\ _eazx) Z / N, N-dimethyl-6-fO r ) I [[rac-(lS)-l- i II II I / 1 cyclopropylethyl]ca _ X. rbamoylamino]pyri N' N N' Y ( / p \x- dine-2-carboxamide VH H1 tn / \. i l-(6-phenyl-2- pyridyl)-3-[rac- (1S)-1- cy cl opropy 1 ethyl ]ureao methyl 3-[3-[[rac- V / (1S)-1- cyclopropylethyl]carbamoylamino]pyra i I I \ zol-l-yl]benzoate V / V H HAttorney Docket No. PTZ-011WOTable 5Chemical Name Structureo3-[3-[[rac-(lS)-l- cyclopropylethyl]ca A- OH rbamoylamino]pyra s C > r^\zol-l-yl]benzoicacid 1 1 L X > Y\ / )V 'hTH H1-[(1S)-1 F- cy cl opropy 1 ethyl ] - 3-[l-[3-fluoro-4- (methylamino)phenyl]pyrazol-3-yl]urea rY H H H X / VH H2-fluoro-4- [3 -[ [rac- F(1S)-1- * ji YN-AX / NH2cyclopropylethyl]carbamoylamino]pyrazol - 1 -y 1 ]b enzami de V H H 0 Vl-[l-[4- F (dimethylamino)-3- I{fluoro-? rA / A / phenyl]pyrazol-3- ■ V yl]-3-[rac-(lS)-l- H \ V H cy cl opropy 1 ethyl ]ureal-(6-methyl-2- pyridyl)-3-[rac- (1S)-1- 1 1 1 1 cy cl opropy 1 ethyl ]urV-< 'N / XN / XN / X' eaVH H0 N, N-dimethyl-3-[3- V / N [[rac-(lS)-l- cyclopropylethyl]carbamoylamino]pyra A A ) zol- 1 -yl]benzamide N' N N vy \ / H H VAttorney Docket No. PTZ-011WOTable 5Chemical Name StructureON-methyl-3-[3- [[rac-(lS)-l- X l’~NH cyclopropylethyl]ca - O p==\ / = A / x rbamoylamino]pyrazol- 1 -yl]benzamide A A A A A )V y. o / H H 1l-[rac-(lS)-l- \\cy cl opropy 1 ethyl ] - i [i / \\ X3- l [ - ° / / / [ - 4 / «(trifluorom ethyl sulf A r * \V H H \ *\ VXA OA F onyl)phenyl]pyrazol / 3 / / -3-yl]urea o / / \\x3-[3-[[rac-(lS)-l- cyclopropylethyl]ca \ r i rbamoylamino]pyrazol- 1 -yl]benzamideOa=> O= 1 l-[l-(4- A X cyclopropylsulfonylphenyl)pyrazol-3- yl]-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ureal-[l-(4- ~ 0 f^\ o ethyl sulfonylphenyl I 1 H — / \ 1! / )pyrazol-3-yl]-3- [rac-(lS)-l- v-A N N N V / n \ / H H 0 cy cl opropy 1 ethyl ]ureal-[l-(3-methyl-4- methyl sulfonyl - phenyl)pyrazol-3- yl]-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ureaAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurel-[l-(4,4- O difluorocyclohexyl) i 9 / ~~\ A pyrazol-3-yl]-3- [rac-(lS)-l- r V— j J| tC A A' I O c w V- cy cl opropy 1 ethyl ]ur H H V - / >Fr ea 1 J Al-[l-[3- < 0 (m et IZ II hyl sulfonylmethyl)phenyl]pyrazol- 3-yl]-3-[rac-(l S)-l - Acy cl opropy 1 ethyl ]ur l ° 1 k cAea v V-A 'N'' N _H ZI / H / A / s / zl-[l-[4- (m ethyl sul WMMW \fonylmethyl)phenyl]pyrazol- 3-yl]-3-[rac-(l S)-l - cy cl opropy 1 ethyl ]ur r )eal-[l-[4- [(dimethylamino)m J \A '♦y ethyl ] pheny 1 ]py razo 1 l-3-yl]-3-[rac-(lS)- 1 1- cy cl opropy 1 ethyl ]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[rac-(lS)-l- pheny 1 ethyl ] py razol A A AAA -3-yl]urea — -N- ''N-' N \ri nAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurel-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[rac-(lR)-l- = 0 f^\ o >== / pheny 1 ethyl ] py razol-3-yl]urea r7 / 1'''NZ1 ''N / L N \\ / H H1-(1- cyclohexylpyrazol- 3-yl)-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ur ■— X J. 'hJ A'N A Hea VH HN \ - / )l-[rac-(lS)-l- cy cl opropy 1 ethyl ] - V 3-[l-[3- ~ 0 A-F (trifluoromethyl)phe rnyl]pyrazol-3- yl]urea A A AV " A vl-[l-(3H H / - chlorophenyl)pyraz = 0r-==\ / = / ol-3-yl]-3-[rac-(l S)- 1- cy cl opropy 1 ethyl ]ur A A AH > ea \ / H Hl-[l-(2-methoxy-4- pyridyl)pyrazol-3 - yl]-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]urea I A £>- AV H HAttorney Docket No. PTZ-011WOTable 5Chemical Name Structure1-[(1S)-1-0HN— cy cl opropy 1 ethyl ] - V / 3-[l-[3- (m ethyl sulfamoyl)phenyl]pyrazol-3- yl]urea v X A X / - \ — 7^ hT N A / H H V— — / 4-[3-[[(lS)-l- cyclopropylethyl]ca § 9 HN- rbamoylamino]pyrazol - 1 -y 1 ] -N -methyl - - \■ / 7"' ANAH HNVv w A O benzamide1-[(1S)-1- = 0 / —A 0 cy cl opropy 1 ethyl ] - 3-[l-(4- 1 JI L W Vl methylsulfonylphen T-Y' N^ N ' Nyl V H H 61 )pyrazol-3-yl]urea1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-[4- y-Y 1 N'' I(m ethyl sulfamoyl)p hT A ^'N / N~J y== / V-X f u \ / H H 0 henyl]pyrazol-3-NdHyl]urea1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(3- methylsulfonylphenyl)pyrazol-3-yl]urea r Vv" 1 N 1HNHN \^ / 1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[2-(2- pyridyl)thiazol-4- Jl JL Jl^ x yl]urea ^ V7 I HT H H N-A'Attorney Docket No. PTZ-011WOTable 5Chemical Name Structure1-[(1S)-1- cy cl opropy 1 ethyl ] - N — / 3-[l-(2- 1 1 L methoxyphenyl)pyra VH HNwzol-3-yl]urea—01-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[2-(3-? rA / -A fluoroph ienyl)thiazol N N V / -4-yl]urea H VH1-[(1S)-1- rB\ F § o r cy cl opropy 1 ethyl ] - i J J 3-[2- (trifluoromethyl)thi\ / LI Li azol-4-yl]urea V ’’ **1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[2-(4- A A A. A-O pyridyl)thiazol-4- N N N _ / / yl]urea \ / H H1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[2-(4-. / -■Ffluorophenyl)thiazol V H H -4-yl]urea VR1-[(1S)-1- -S cy cl opropy 1 ethyl ] - £3-[2-(2- i1r fluorophenyl)thiazol-4-yl]ureaH V HAttorney Docket No. PTZ-011WOTable 5Chemical Name Structure1 -(1 -benzylpyrazol- 3-yl)-3-[(lS)-l- i l lcy cl opropy 1 ethyl ]ur V-r'' ■'N'' ''N' " N \ _ ea V H «1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[2-(3- pyridyl)thiazol-4- yl]urea N N N _ / / V H H1-[(1S)-1- s 0cy cl opropy 1 ethyl ] - 3-(2-methylthiazol- * I JI4-yl)urea If NVH H1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-(l-pyrimidin-2- A 1 / H~'A J ylpyrazol-3-yl)urea s — s' N 1 Z V H HN— 1-[(1S)-1-,0— cy cl opropy 1 ethyl ] -50 r=^\ / == / 3-[l-(3,4- 1 I L IM'—Z \ dimethoxyphenyl)p N Nyrazol-3-yl]urea H \ _ / / VH HAttorney Docket No. PTZ-011WOTable 5Chemical Name Structureli [ LL 1-[(1S)-1- cy cl opropy 1 ethyl ] - ~ c3-[l-(2,2,2- trifluoroethyl)pyraz A Jol-3-yl]urea 'ITV H1-[(1S)-1- / £cy cl opropy 1 ethyl ] - 3-[l-(4-fluoro-3- methyl-? I / _ L \ phenyl)pyrazol-3- N NT N \ _ / / yl]urea V H H1-[(1S)-1- O — cy cl opropy 1 ethyl ] - 3-[l-(4-fluoro-3- methoxy- i y~ / ==^.Fphenyl)pyrazol-3- A lyl]urea VHH1-[(1S)-1- i 9 AA / A cy cl opropy 1 ethyl ] - 3-[l-(3- A A / methoxyphenyl)pyr V H Hazol-3-yl]urea0— - F1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(2,2- difluoroethyl)pyraz l JI Ln--vol-4-yl]urea\ \ / / L nJ L ni1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(4- methoxyphenyl)pyrazol-3-yl]urea yH H \Attorney Docket No. PTZ-011WOTable 5Chemical Name Structure1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-(4-phenyloxazol- 2-yl)urea r- / X N JL " NT A N AX _ / )V H H1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-(2-phenyltriazol- VV J. '-N" JL N / X4-yl)urea V:N / NAH H V / 1-[(1S)-1- = 0cy cl opropy 1 ethyl ] - H / ==, 3-(5-phenyl-l,3,4- oxadiazol-2-yl)urea i l l A V H H1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-(2-phenylthiazol- A4-yl)urea r- / N A N AMNAX / )VH H1-[(1S)-1- = 0cy cl opropy 1 ethyl ] - N-°v / =\ 3-(5-phenyl-l,2,4- _ x A AXA } oxadiazol-3-yl)urea V N N N _ / H H1-[(1S)-1- • o N-'H / ==X cy cl opropy 1 ethyl ] - J3-(5-phenyl-l,3,4- jl 1 VA \ thiadiazol-2-yl)urea — 'N'' ''tA's A _ / V H HAttorney Docket No. PTZ-011WOTable 5Chemical Name Structure1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(4- i I L; N~Y pyridyl)pyrazol-3 - yl]urea V H H1-[(1S)-1- cy cl opropy 1 ethyl ] - 3 -(5 -phenyl oxazol - 2-yl)urea rZ i'N'''' T ^N' Ju _ / \VH1-[( S)- - >H1 1rNcy cl opropy 1 ethyl ] - 3-(2-phenylthiazol- 5-yl)urea A J[ 1 ) 1 VHH A ' z ' 1- ( S - - cy cl opropy 1 ethyl ] - 3-(l- | 0 / ==, phenylimidazol-4-r7 / XN / \ / x'< / _ / yl)urea V H H1-[(1R)-1- cy cl opropy 1 ethyl ] - 3-(l- phenylimidazol-4- J I L, N— < \ yl)urea \ / H H1-[(1S)-1- X Ccy cl opropy 1 ethyl ] - 3-[l-(2- pyridyl)pyrazol-3 - yl]urea v-r AV NHJ X y. Fl XrNN--Z )Attorney Docket No. PTZ-011WOTable 5Chemical Name Structure1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-(4-phenylthiazol- z 1. x X f2-yl)urea V H H1-[(1S)-1- § 0 A\ / ^N cy cl opropy 1 ethyl ] - 3-(l-pyrimidin-5- ylpyrazol-3-yl)urea T—f N A N' XA N X V / )V H HN1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(3- pyridyl)pyrazol-3 - i 1 A / A >X — S N" Nyl]urea \ / H HN1-[(1S)-1- cy cl opropy 1 ethyl ] - § 9 AX3-[l-(4- fluorophenyl)pyrazo I 1 X zN~<\ X-F l-3-yl]urea V H Hp 1-[(1S)-1- cy cl opropy 1 ethyl ] - = 0 p^\ / =< / 3-[l-(3- fluorophenyl)pyrazol-3-yl]urea A A X / AV H HF1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(2- fluorophenyl)pyrazo 1 1 r> Al-3-yl]urea [f fl- VzAttorney Docket No. PTZ-011WOTable 5Chemical Name Structure1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-(3,4- difluorophenyl)pyra J Izol-3-yl]urea V H H1-[(1S)-1- -X / cy cl opropy 1 ethyl ] - ~ 0 rn / — N3-[l-[2- (dimethylamino)eth — 1 Jy 1 ] py razol -3 -y 1 ]urea - |C NVHH1-[(1R)-1-. 0cy cl opropy 1 ethyl ] - 3 -( 1 -phenylpyrazol- 4-yl)urea A X / M )\ / H H1-[(1S)-1- cy cl opropy 1 ethyl ] -? / ^y 3 -( 1 -phenylpyrazol- 4-yl)urea A JV V7 M H H1-[(1R)-1- cy cl opropy 1 ethyl ] - 3-[l-[2- (dimethylamino)ethy 1 ] py razol -3 -y 1 ]urea VH H1-[(1S)-1- cy cl opropy 1 ethyl ] - J3-(5-methyl-l- fphenyl-pyrazol-3-C1 \ yl)urear7 / XN / VHnAttorney Docket No. PTZ-011WOTable 5Chemical Name Structureti ti \ / 1-[(1R)-1- / yj tf cy cl opropy 1 ethyl ] - 3-(5-methyl-l- \ phenyl-pyrazol-3 I 1 L MM- yl)urea / %\ w / \ L “i LJ ~~ n11-[(1R)-1- cy cl opropy 1 ethyl ] - 3-(4-methyl-l- \Z Q X1Zphenyl-pyrazol-3- X / yl)urea( oyy= ««» \l-(4-methyl-l- / ..phenyl-pyrazol-3- / yl)-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ur r-< X N XS N' 'N ' ea V H H\ / V T| T|FI IL 1 i4 F\ / H HX 1 J. / )-( '? IS ST N ^N' W F \ / H HAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurei o A\— Vz1 1 X.H H N / N'~'X 1_ / V-Z \-n \0uHs 0 fA. HO f 1 I V Y - V~~A N" N' N V / \ A V H H U-0 A A AM XVX i n'N vZA F = o F=\ / ==Nj Y 1 '^' X N / M VZ XX AO0HHi y N-X \ / T — \ / / — X-OH 7 N N N A. X \ \ / H H \\ / H H§ 9 A* ZMIA JL. ) — Z0H\ / H HFs s 9 |[ 1 AX N~A xA V / zV H Hvy^vx 0HAttorney Docket No. PTZ-011WOTable 5Chemical Name StructureX F O o X1A A JL / \\ A- TA J MM* A O J. ~OH Vy? f T A 21H H ■■ / J 1Vo A Az: AV H / H / / V \-F M^ U / X ZI 2 \ F FrX XZI 1 <yfiifl * / V Z(S)-l-(l- $ cyclopropylethyl)- i V> ' Li 93-(l-(5-(2- i 0 / , N— / \ / zhydroxypropan-2- v VVV H-V H 'S / V ZV-O ~ yl)pyridin-2-yl)-lH- X H b X *T1 pyrazol-3-yl)urea(S)-l-(l- cyclopropylethyl)- 3-(l-(6-(2- hydroxypropan-2- yl)pyri din-3 -yl)- 1 H- pyrazol-3-yl)ureal-[2-[6-(l-hydroxy- 1 -methyl -ethyl)-3- pyridyl]thiazol-4- yl]-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ureal-[2-[4-(l- hydroxy cyclopropyl)pheny 1 ] thi azol -4- yl]-3-[rac-(lS)-l- cy cl opropy 1 ethyl ]ureaAttorney Docket No. PTZ-011WOTable 5Chemical Name Structurex u« l-[l-[4-(l- O hydroxy cyclopropyl? 9 HO )phenyl]pyrazol-3- i. Ji k / N-< kA yl]-3-[rac-(lS)-l- 'X FT' N \ 7 cy cl opropy 1 ethyl ]ur y H H ZKAVea I 1Xl-[rac-(lS)-l- OHPcy cl opropy 1 ethyl ] - 13-[l-[2-[rac-(lS)- A4 — c 2,2 A z zA\ ’,2-trifluoro-l- hydroxy-l-methyl- L t\ethyl]-4-FN N N V / pyridyl]pyrazol-3 - \ V / H Hyl]urea\l-[rac-(lS)-l- / OHFcy cl opropy 1 ethyl ] - 3-[l-[2-[rac-(lR)- \2,2,2-trifluoro-l- hydroxy-l-methyl- ethyl]-4- X A A / MTv —pyridyl]pyra N H \zol-3 - V H Hyl]ureal-[l-[4-(3- hydroxyoxetan-3 -? 9 HOI I Lyl)phenyl]pyrazol- 3-yl]-3-[rac-(l S)-l - V J" 1 X \ / H H I— O cy cl opropy 1 ethyl ]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[6-[rac-(lR)- x 1 X2,2,2-trifluoro-l- / NA A-P> Hhy droxy-1 -methylV H Hethyl] -3- F F pyridyl]pyrazol-3 - yl]ureal-[rac-(lS)-l- cy cl opropy 1 ethyl ] - 3-[l-[6-[rac-(lS)- 2,2,2-trifluoro-l- hy droxy-1 -methyl-Attorney Docket No. PTZ-011WOTable 5Chemical Name Structureethyl] -3- pyridyl]pyrazol-3 - yl]urea1-[(1S)-1- cy cl opropy 1 ethyl ] - 3-[l-[5-[(lR)-2,2,2- x^trifluoro- 1 -hydroxy- / l-methyl-ethyl]-2- 1IMI IIM “I"pyridyl]pyrazol-3 - \ \ )Q=yl]urea / / MMtMN1-[(1S)-1- \cy cl opropy 1 ethyl ] - # a3-[l-[5-[(lS)-2,2,2- trifluoro- 1 -hydroxy- l-methyl-ethyl]-2- pyridyl]pyrazol-3 - iJyl]urea ' f'' z rL I j IIl-[rac-(lS)-l- T Fcy cl opropy 1 ethyl ] - 13-[2-[l-(2,2,2- ■ O,,'X L x % ^ A ~n~~ _.\ trifluoroethyljimida \ I O ■n | ozol-4-yl]thiazol-4- A X >-< J X " HF5MM ucyl]urea \ / H HN

[0095] 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.

[0096] In some embodiments, identifying a subject comprises diagnosing a subject by sequencing the subject’s POLG gene.

[0097] In some embodiments, POLG gene mutation is, or the sequence of the subject’s POLG gene reveals, one or more mutations in the POLG gene selected from the group consisting of: R3P, S28C, G11D, Q43R, Q45R, Q49E, Q68X, A(CAG)n, S64L, L79F, L83P, H110Y, P116Q, D122Y, D136E, A143V, P163S, R193Q, C224Y, R227P, R227W, R232G, R232H, W235X, P241L, L244P, T251I, G268A, R275X, R275Q, H277L, Y282D,Attorney Docket No. PTZ-011WOG303R, L304R, S305R, Q308H, R309L, R309H,-W312R, K319E, P324S, T326fs61X, T326fs387X, W347_L356del, W347fs356X, E358A, R374X, G380D, E386H, R386C, L392V, L392W, R417T, R417X, C418R, L424Gfs28X, L424X, G426S, L428P, G426S, M430L, G431V, S433C, M340L, G431V, S433C, Q449X, T452X, Y452X, L463F, M464T, A467T, N468D, Q497H, K498T, S511N, K512M, G517V, R546C, K561M, R562Q, H569Q, R574W, R579W, W585X, P587L, G588D, P589L, L591F, R597W, K601E, M603L, L605R, R617C, G621D, L623W, P625R, R627W, R627Q, R628Q, P648R, E662K, R709X, Q715X, R722H, N736S, G737R, G746S, W748S, F749S, L752P, H754Q, K755E, G763R, P765T, A767D, K768E, G785fs21X, R790H, M797del, A804T, R807P, R807C, R807H, Y831C, G848S, T849X, T849H, T851A, R852C, R852H, R853Q, R853W, V855A, V855L, A862T, N864S, R869Q, E873X, Q879H, T885S, L886P, G888S, G888D, A889T, D890A, E895G, F907I, T914P, T914A, W918R, M919T, G923D, K925fsX, K925Rfs42X, D930N, H932Y, S933R, R943H, R943C, H945L, K947R, Y951N, R953C, Y955C, A957S, A957P, A957V, F961S, A962T, R964C, L965X, L966R, G975X, Y995C, S998L, W1020X, Q1024X, V1044A, R1047Q, R1047W, K1050X, G1051R, G1052S, G1052D, E1054fs, P1073L, G1076V, C1077G, I1079L, S1080T, S1080I, R1081P, R1091Q, S1095G, S1095R, R1096C, R1096H, SI 104C, SI 104F, Al 105T, VI 1061, Hl HOY, LI 113P, R1128H, Hl 134R, El 136K, R1138C, R1142W, El 143G, El 145G, DI 145GfsX9, R1146C, QI 154R, Ml 163R, Fl 1641, L1173fsX, S1176L, D1184N, D1184L, I1185T, R1187W, Cl 188R, KI 191N, KI 191R, D1196N, T1199X, G1205A, Y1210fs6X, Q1214X, Y1210fsl216X, S1230F, Q1236H, X1240Q / Y + 35aa, and any combination thereof.

[0098] In some embodiments, the one or more mutations is R232H, R309C, A467T, W748S, G848S, Y955C, E1143G, T251I-P987L, A467T and G484S, W748S + El 143G and R232H, G303R and A467T, G737R and R232H, F197S and T914P, A467T and R574W, Y955C, T251I and P587L, W748S and El 143G, or any combination thereof. In some embodiments, the one or more mutations is A467T, W748S, G848S, R232H, and any combination thereof. In one embodiment, the one or more POLG mutations is R232H. In one embodiment, the one or more POLG mutations is R309C. In one embodiment, the one or more POLG mutations is A467T. In one embodiment, the one or more POLG mutations is W748S. In one embodiment, the one or more POLG mutations is G848S. In one embodiment, the one or more POLG mutations is Y955C. In one embodiment, the one orAttorney Docket No. PTZ-011WOmore POLG mutations is E1143G. In one embodiment, the one or more POLG mutations is T251I-P987L. In one embodiment, the one or more POLG mutations is A467T and G484S. In one embodiment, the one or more POLG mutations is W748S and E1143G. In one embodiment, the one or more POLG mutations is W748S, El 143G and R232H. In one embodiment, the one or more POLG mutations is G303R and A467T. In one embodiment, the one or more POLG mutations is G737R and R232H. In one embodiment, the one or more POLG mutations is F197S and T914P. In one embodiment, the one or more POLG mutations is A467T and R574W. In one embodiment, the one or more POLG mutations is T251I and P587L.

[0099] In some embodiments, the POLG mutation results in one or more mitochondrial DNA (mtDNA) deletions, reduced mtDNA levels, a reduction in mtDNA POLy activity, low processivity of the POLy, a defect in the mtDNA-binding function of POLy, a decrease in the mtDNA-binding affinity of POLy, or any combination thereof. In some embodiments, the POLG mutation results in reduced mtDNA levels. In some embodiments, the POLG mutation results in a defect in the mtDNA-binding function of POLy. In some embodiments, the POLG mutation results in a decrease in the mtDNA-binding affinity of POLy.[000100] In some embodiments, the POLG mutation results in lower levels of mtDNA copy number in a tissue specific cell type of the subject compared to the tissue specific cell type in a subject who does not have a POLG mutation. In some embodiments, tissue specific cell type is selected from the group consisting of a fibroblast, hepatocyte, neuronal, and muscle.[000101] In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof: (a) results in upregulating levels of healthy 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 mitochondrial DNA (mtDNA) production in the subject; (e) results in an increase in mitochondrial DNA (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) improves the processivity of a POLy protein in the subject; (i) increases cellular respiration in the subject; (j) shifts ATP production rate to favor oxidative phosphorylation in the subject; (k) results in improved liverAttorney Docket No. PTZ-011WOhealth for the subject; (1) results in an increase of mtDNA levels in the subject, or (m) any combination thereof. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in upregulating levels of healthy mtDNA in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in an increase of mtDNA levels in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in dosedependent increases in mtDNA production in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, improves mtDNA recovery following depletion in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in an increase in mitochondrial DNA (mtDNA) production in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in an increase in mitochondrial DNA (mtDNA) copy number per cell in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in restoration of mtDNA levels in the subject, and related improvement in cellular function. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in an increase in mtDNA production in subject-derived fibroblasts. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, improves the processivity of a POLy protein in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, increases cellular respiration in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, shifts ATP production rate to favor oxidative phosphorylation in the subject. In some embodiments, administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof, results in improved liver health for the subject.[000102] In some embodiments, the increase in the mtDNA copy number per cell is at least about 5%, at least about 10%, at least about 15%, at least about 20%, at least about 25%, atAttorney Docket No. PTZ-011WOleast 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’s cell prior to administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof.[000103] 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.[000104] In some embodiments, the improvement of the processivity of POLy is 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 protein prior to administration of the compound of formula I, II, III, IV, or V, or a pharmaceutically acceptable salt thereof.[000105] 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,Attorney Docket No. PTZ-011WOabout 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, about 1925 mg, about 1950 mg, about 1975 mg, or about 2000 mg.[000106] 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[000107] In some embodiments, the compound is administered once per day. In some embodiments, the compound is administered twice a day. In some embodiments, the compound is administered with food.[000108] In some embodiments, the PMD or MDDS disorder characterized by a mutation in POLG is selected from the group consisting of Alpers-Huttenlocher syndrome (AHS), autosomal dominant progressive external ophthalmoplegia (adPEO), autosomal recessive progressive external ophthalmoplegia (arPEO), myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathyAttorney Docket No. PTZ-011WOspectrum (ANS), mitochondrial recessive ataxia syndrome (MIRAS), progressive external ophthalmoplegia (PEO), mitochondrial encephalomyopathy (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE), sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO), and spinocerebellar ataxia with epilepsy (SCAE).[000109] In some embodiments: (a) the MDDS disorder characterized by a mutation in POLG is ataxia neuropathy spectrum (ANS) and the POLG mutation is W748S; (b) the MDDS disorder characterized by a mutation in POLG is Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia, Ataxia neuropathy spectrum or sensory ataxia neuropathy dysarthria and ophthalmoplegia and the POLG mutation is A467T; (c) the MDDS disorder characterized by a mutation in POLG is AHS and the POLG mutation is Gly848, G848S, T851A, R852C, R853Q, or any combination thereof; (d) the MDDS disorder characterized by a mutation in POLG is AHS and the POLG mutation is G1 ID, Q68X, L79F, L83P, A143V, C224Y, R227P, R227W, R232G, R232H, W235X, L244P, T251I, H277L, Y282D, G303R, L304R, S305R, R309H, T326fs387X, W347fs356X, E358A, R374X, E386H, R417T, R417X, C418R, L424X, G426S, L428P, A467T, G517V, K561M, H569Q, R574W, P587L, P589L, L605R, P625R, R627Q, Q715X, R722H, G737R, W748S, F749S, L752P, H754Q, A767D, R790H, M797del, R807H, G848S, T849X, T851A, R852C, R852H, R853Q, V855L, E873X, Q879H, T885S, L886P, G888S, G888D, E895G, T914P, T914A, K925fsX, D930N, R943C, A957P, A957V, L966R, G975X, W1020X, Q1024X, V1044A, R1047W, K1050X, P1073L, C1077G, S1080I, R1091Q, S1095R, R1096C, R1096H, Hl HOY, LI 113P, Hl 134R, El 136K, El 143G, DI 145GfsX9, Ml 163R, LI 173fsX, 11185T, R1187W, C1188R, K1191N, K1191R, Y1210fsl216X,, and any combination thereof; (e) the MDDS disorder characterized by a mutation in POLG is PEO and the POLG mutation is T251I and P587L amino acid substitutions and / or Y955C; (f) the MDDS disorder characterized by a mutation in POLG is autosomal dominant PEO and the POLG mutation is S511N, G293D, S933R, R943C, R943H, H945L, K947R, R953C, Y955C, A957S, F961S, I1079L, S1095R, Al 105T, and any combination thereof; (g) the MDDS disorder characterized by a mutation in POLG is autosomal recessive PEO and the POLG mutation is R3P, S28C, T2511, R275X, R275Q, L304R, Q308H, R309L, K319E, R386C, M430L, L463F, A467T, N468D, G517V, R574W, P587L, R597W, M603L, R627W, P648R, R722H, G737R, G746S, G763R, c.2354Gins, G848S, R853W, A862T, N864S, R869Q, W918R,Attorney Docket No. PTZ-011WOM919T, H932Y, S998L, R1047W, G1051R, R1081P, VI 1061, R1138C, Fl 1641, S1176L, D1184L, D1184N, K1191N, T1199X, Q1214X, X1240Q / Y + 35aa, and any combination thereof; (h) the MDDS disorder characterized by a mutation in POLG is sporadic PEO and the POLG mutation is P163S, R227W, G268A, W312R, G380D, L424X, G431V, S433C, Y452X, R562Q, R579W, W585X, R709X, R807P, A889T, R1047Q, G1076V, R1096C, SI 104F, SI 104C, and any combination thereof; or (i) the MDDS is ataxia neuropathy syndrome (ANS), MIRAS, SANDO, or SCAE and the POLG mutation is G1 ID, D122Y, L304R, G426S, M464T, A467T, Q497H, L591F, K601E, R627Q, R627W, P648R, N736S, W748S, G763R, P765T, K768E, R807C, A862T, R869Q, Y951N, A962T, R964C, L965X, S1080T, El 143G, and any combination thereof.[000110] 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, generalized status epilepticus, refractory convulsive status epilepticus, developmental delay, neurodevelopmental regression, renal dysfunction, hypotonia, epilepsia partialis continua, and any combination thereof.[000111] 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.[000112] 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.[000113] 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.[000114] In some embodiments, the subject to be treated is: (a) a pediatric patient less than 12 years old; (b) an adolescent over an age of 12 years old through an adult up to age 40; or (c) an adult over age 40. In some embodiments, the subject to be treated is a paediatricAttorney Docket No. PTZ-011WOpatient less than 12 years old. In some embodiments, the subject to be treated is an adolescent over an age of 12 years old through an adult up to age 40. In some embodiments, the subject to be treated is an adult over age 40.[000115] In some embodiments, 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, penetrates the central nervous system (CNS). In some embodiments, a compound is selected from the group consisting of l-((S)-8-chlorochroman-4-yl)-3-(2-(l-hydroxyethyl)thiazol-4-yl)urea, l-((R)-8-chlorochroman-4-yl)-3-(2-(l -hydroxy ethyl )thi azol -4-yl)urea, l-[2-(3-methyl-l,2,4-thiadiazol-5-yl)thiazol-4-yl]-3-[rac-(4S)-8-chloro-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]urea, (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, l-[rac-(lS)-l-cyclopropylethyl]-3-[l-[3-[rac-(lR)-2,2,2-trifluoro-l-hydroxy-ethyl]phenyl]pyrazol-3-yl]urea, and l-[(4S)-8-chlorochroman-4-yl]-3-(l-phenylpyrazol-3-yl)urea, or a pharmaceutically acceptable salt thereof, penetrates the CNS. In some embodiments, 1 -((S)-8-chlorochroman-4-yl)-3- (2-(l -hydroxy ethyl)thiazol-4-yl)urea penetrates the central nervous system (CNS).III. Definitions[000116] 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.[000117] 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., “suchAttorney Docket No. PTZ-011WOas”) provided herein, is intended merely to better illuminate the embodiments and does not pose 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.[000118] 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 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.[000119] “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.[000120] 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”).[000121] 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 self-administration and the administration by another.[000122] 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.Attorney Docket No. PTZ-011WO[000123] 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.[000124] 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.[000125] The terms “pharmaceutically-acceptable,” “physiologically-tolerable,” and grammatical variations thereof, as they refer to compositions, carriers, diluents, and reagents,Attorney Docket No. PTZ-011WOare used interchangeably and represent that the materials are capable of administration to or upon 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, N-methylglucamine, 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.[000126] 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.Attorney Docket No. PTZ-011WO[000127] 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).[000128] 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.[000129] “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.[000130] 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. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and Ce alkyl.[000131] 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.[000132] 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.Attorney Docket No. PTZ-011WO[000133] 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, tertpentyl, 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).[000134] 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).[000135] As used herein, the term “amino” refers to a group of formula -NH2.[000136] 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.[000137] 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.[000138] 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-Attorney Docket No. PTZ-011WObromopropyl, 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.[000139] 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.[000140] 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 rings 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).[000141] 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),Attorney Docket No. PTZ-011WOand 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 moi eties 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 moi eties having 1-2 ring nitrogen atoms (e.g., pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, or pyrazolyl).[000142] 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 independently 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- 1,1 -di oxido-2 / 7-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,Attorney Docket No. PTZ-011WO3-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).[000143] 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 members 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 fivemembered 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 firomN, 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 fromN, O, and S. Exemplary six-membered ring hetero aryls include, without limitation, pyridyl, pyrazinyl, pyrimidinyl, triazinyl, and pyridazinyl. Ring-formingAttorney Docket No. PTZ-011WOcarbon 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 moieties 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 containing 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.[000144] 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.Attorney Docket No. PTZ-011WO[000145] 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).[000146] 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[000147] Example 1.[000148] The purpose of this example was to evaluate the ability of compounds described herein to correct the processivity of POLy.[000149] A DNA synthesis assay was performed on a single-stranded DNA template using a 20-mer oligonucleotide hybridized to M13mpl8 single-stranded DNA template. Reactions were performed at a final volume of 10 pL. Each reaction contained 0.5 nM of template DNA, 25 mM Tris-HCl, pH 8.0, 1 mM TCEP, 10 mM MgCl2, 0.1 mg / mL BSA, 100 pM of all four dNTPs, 0,02% TRITON X-100, 200 nM mtSSB (calculated as a tetramer), 0.5 nM of the specified POLgA variants, and 0.65 nM POLgB (calculated as a dimer). Reaction mixtures were distributed into microplates (384-well) with wells containing compounds prepared from 10 mM compound stocks in 100% DMSO (final compound concentrations indicated in FIG. 2B). Equal amounts of DMSO without any compound were added to positive and negative control reactions. The reactions were incubated at 37 °C for 2 h in a VWR INCU-Line incubator and terminated by the addition of 10 pL of 50 mM EDTA, 0,02% TRITON X-100, and SYBR Green I (1: 5000) followed by incubation for 20 min at room temperature. The fluorescence signal was analyzed using a BMG PHERAstar microtiter plate reader (between 485-520 nm).[000150] Each compound concentration series (10 step half-log dilution) was plated in duplicate. Nonlinear regression analysis (variable slope, 4 parameters) was used for the curveAttorney Docket No. PTZ-011WOfitting to determine AC50 value and max response (curve plateau) in which POLg mutant response is shown as relative to WT response.[000151] Data shown in FIG. 2B shows that compounds described herein corrected the processivity of a wide range of POLy protein (e.g., POLy A467T, POLy G848S, POLy W748S, POLy R309C, and POLy Y955C), with the graph shown depicting % WT Activity vs Log10concentration (pM).Table 6POLy mutantPOLy A467T 251 nMPOLy G848S 204 nMPOLy W748S 90 nMPOLy R309C <3 nMPOLy Y955C <3 nM[000152] The data demonstrates the effectiveness of the compounds described herein to correct the processivity of a wide range of POLy protein.[000153] Example 2.[000154] The purpose of this example was to evaluate the ability of compounds described herein to increase the amount of mtDNA in POLy mutants.[000155] Primary skin fibroblasts from two patients with mutations in POLG(NP 001119603.1) were obtained from the Swedish Biobank. Patient 1 exhibited compound heterozygosity for mutations p.[Ala467Thr] and [Gly848Ser], while patient 2 harbored compound heterozygous mutations p.[Trp748Ser+Glul 143Gly] and p.[Arg232His], Fibroblasts 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 was induced by adding 50 ng / mL ethidium bromide (EtBr) to the culture medium for 4 days, followed by a return to EtBr-free media. Five compounds (C1-C5) were added at concentrations of 50 nM, while vehicle (0.1% DMSO) served as a control. Treatment was performed for 5 days.[000156] Cl= (S)-4-(3-(3-(8-chlorochroman-4-yl)ureido)-lH-pyrazol-l-yl)-N-methylbenzamideAttorney Docket No. PTZ-011WO[000157] C2= l-[l-[4-(l-amino-l-methylethyl)phenyl]pyrazol-3-yl]-3-[(4S)-8-chlorochroman-4-yl]urea[000158] C3= l-[(4S)-8-chlorochroman-4-yl]-3-[l-[4-(l-hydroxy-l-methyl-ethy l)pheny 1 ] py razol -3 -y 1 ]urea[000159] C4= 1 -[(4S)-8-chlorochroman-4-yl]-3-[l-[4-[2, 2, 2-trifluoro-l -hydroxyethyl ]phenyl ] py razol -3 -y 1 ]urea[000160] C5= l-[(4S)-8-chlorochroman-4-yl]-3-[2-(4-methylsulfonylphenyl)thiazol-4-yl]urea[000161] Cll = 1 -((S)-l-cy cl opropylethyl)-3-(l-(4-((S)-2, 2, 2-trifluoro-l -hydroxy ethyl)phenyl)-lH-pyrazol-3-yl)urea[000162] C12 = (S)-l-(8-chl oro-3, 4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl)-3-(2-(pyridin-2-yl)thiazol-4-yl)urea[000163] C13 = (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[000164] Compounds C1-C5, each at 50 nM, resulted in an increase in mtDNA in A467T / G848S (first bar in each pair) and W748S + El 143G / R232H (second bar in each pair) mutants in the patient-derived fibroblasts as compared to a control (FIG. 3).[000165] Low mtDNA levels are the root-cause of disease presentation and progression, and therefore restoring mtDNA should lead to improvements in patient cellular function.[000166] Example 3.[000167] The purpose of this example was to evaluate the ability of compounds described herein to bind specifically to POLy using a differential scanning fluorimetry assay.[000168] The fluorescent dye SYPRO Orange was used to monitor temperature-induced unfolding of POLg. Briefly, the experiment was performed in 384-well PCR plates and individual reactions contained wild-type or mutant proteins (final concentration 0.5 pM), 5* SYPRO Orange, 20 mM Tris-HCl, pH 8.0, and 1 mM DTT, in the absence or presence of 10 pM of compound. Differential scanning fluorimetry was performed in a CFX Opus 384 Real-Time PCR System using the CFX Maestro real time software (BioRad). Scans were recordedAttorney Docket No. PTZ-011WOusing the HEX emission filter (560-580 nm) between 4 and 95 °C in 0.5 °C increments with a 5s equilibration time. The melting temperature (Tm) was determined from the first derivative of a plot of fluorescence intensity versus temperature.[000169] l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea binds specifically to POLy (FIGs. 4A-C). FIG. 4A shows the results of the POLy WT Thermal Shift Assay of Relative fluorescence unit (RFU) (normalized) vs temperature (°C) of wild time (WT) and WT + l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea, in patient-derived fibroblasts. FIG. 4B shows the POLy mutant Thermal Shift Assay of RFU (normalized) vs temperature (°C) of mutant G848S and mutant G848S + l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea, in patient-derived fibroblasts. FIG. 4C shows the results of the POLy WT thermal shift assay of Fluorescence (norm) vs temperature (°C) for Dimethylsulfoxide (DMSO) and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea.[000170] Example 4.[000171] The purpose of this example was to evaluate the ability of compounds described herein to improve mtDNA recovery in POLy mutants following depletion.[000172] WT Normal Human Dermal Fibroblasts (NHDF) were obtained from PromoCell (C-12302). 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 EtBr to the culture medium for up to 7 days, followed by a return to EtBr-free media. l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea was added at concentrations of 1 pM, while vehicle (0.01% DMSO) served as a control.[000173] Proliferating WT cells did not show a different recovery speed of mtDNA when treated with DMSO and 1 pM of the compound (FIG. 5). In proliferating WT cells, POLy activity is not rate-limiting.[000174] Example 5.[000175] The purpose of this example was to evaluate the ability of compounds described herein to accelerate mtDNA recovery in POLy mutants following depletion.Attorney Docket No. PTZ-011WO[000176] Fibroblasts from healthy donors (FIG. 6A and C) and patient-derived fibroblasts harboring POLy (NP 001119603.1) mutation g p.[Ala467Thr];[Gly848Ser] (FIG. 6B and D) 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 EtBr to the culture medium for up to 7 days (T7), followed by quiescence induction by serum starvation (0.1 % FBS) and contact inhibition for 3 days with or without EtBr (T7+T3) (T7+3). All fibroblasts were treated with 1 pM of 1-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea or 0.01% DMSO as vehicle (control) for up to 14 days. Cells were harvested after 3, 5-, 7-, 10- and 14-days posttreatment.[000177] For assessing the effect of compound on mtDNA levels, cell pellets were collected from 3 individual wells per cell line and treatment. Cell pellets were stored at -20°C until DNA extraction and mtDNA copy number determination by qPCR. DNA samples were extracted from cell pellets with the Zymo Genomic DNA Clean & Concentrator- 10 kit. DNA samples were then 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 500 nM of forward and reverse primer each. mtDNA was amplified using primers specific to human CYTB gene in the mitochondrial genome, and 18S gene as nuclear reference gene. Results are calculated as mtDNA / nuclear (nDNA) and shown as normalized to undepleted samples.[000178] The compounds described herein (e.g., l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea) accelerate mtDNA recovery in quiescent WT and POLy mutant fibroblasts (FIGs. 6A-6D, T7: 7-day depletion in proliferation phase; T7+3: 7-day depletion in proliferation phase and 3-day recovery in quiescent phase; and T7+T3: 7-day depletion in proliferation phase and 3-day depletion in quiescent phase). FIG. 6A shows EtBr depletion in proliferation phase for WT T7 +3 quiescent, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for the compound at 1 pM and DMSO. FIG. 6B shows EtBr depletion in proliferation phase for A467T / G848S T7+3 quiescent, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for the compound at 1 pM (repeated twice), and DMSO (repeated twice). FIG. 6C shows EtBr depletion in proliferation and quiescentAttorney Docket No. PTZ-011WOphase for WT T7 + T3, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for the compound at 1 pM (repeated twice) and DMSO (repeated twice). FIG. 6D shows EtBr depletion in proliferation and quiescent phase for A467T / G848S T7+3 quiescent, mtDNA / nDNA normalized to undepleted vs time (0-14 days), for the compound at 1 pM (repeated twice), and DMSO (repeated twice). Quiescent WT cells show recovery of mtDNA regardless of DMSO or compound treatment after 7-day depletion in proliferation phase, but more recovery of mtDNA when treated with compound, after a total of 10-day depletion. Quiescent A467T / G848S cells show more recovery of mtDNA when treated with compounds after 7-day depletion in proliferation phase, but no recovery of mtDNA at all after a total of 10-day depletion.[000179] Example 6.[000180] The purpose of this example was to evaluate the ability of compounds described herein to accelerate mtDNA recovery in POLy mutants following depletion, in a concentration-dependent manner.[000181] Patient-derived fibroblasts harboring mutations in POLy (NP 001119603.1) carrying p.[Trp748Ser; Glul 143Gly]; [Trp748Ser; Glul 143Gly] in FIG. 7A and p.[Thr251Ile; Pro587Leu];[Trp748Ser; Glul 143Gly] in FIG. 7B 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 EtBr to the culture medium for up to 7 days (T7), followed by quiescence induction by serum starvation (0.1 % FBS) and contact inhibition for 3 days in the presence of EtBr (T7+T3). All fibroblasts were treated with 0.03, 0.1, 0.3, 1, 3 pM of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea or 0.01% DMSO as vehicle (control). After 5 and 15 days (and 21 days for FIG. 7A), cells were harvested for mtDNA determination.[000182] For assessing the effect of the compound on mtDNA levels, cell pellets were collected from 2 individual wells in FIG. 7A and one individual well in FIG.7B per treatment per time point. Cell pellets were stored at -20°C until DNA extraction and mtDNA copy number determination by qPCR. DNA samples were extracted from cell pellets with the Zymo Genomic DNA Clean & Concentrator- 10 kit. DNA samples were then diluted (at least 1:5) with nuclease-free water before qPCR. qPCR was performed in triplicate on a 384-wellAttorney Docket No. PTZ-011WOreaction plate. Each PCR reaction (final volume 10 pL) contained 1-10 ng DNA, lx SYBR Green PCR master mix, and 500 nM of forward and reverse primer each. mtDNA was amplified using primers specific to human CYTB gene in the mitochondrial genome, and 18S gene as nuclear reference gene. Results are calculated as mtDNA / nuclear (nDNA) and shown as normalized to undepleted samples.[000183] FIGs. 7A & B demonstrate that the compounds described herein (e.g., 1 -((S)-8-chlorochroman-4-yl)-3 -(2-((S)- 1 -hydroxy ethyl)thiazol-4-yl)urea) accelerate mtDNA recovery in a concentration dependent manner (T7: 7-day depletion in proliferation phase, and T7+T3: 7-day depletion in proliferation phase and 3-day depletion in quiescent phase).FIG. 7A shows a graph of EtBr-depleted quiescent cells, time course and dose response, for W748S+E1143G / W748S+E1143G mutants (patient derived fibroblasts), with mtDNA / nDNA normalized to undepleted vs drug concentration, for 5, 15, and 21 days, and FIG. 7B shows a graph of EtBr-depleted quiescent cells, time course and dose response, for T251I+P587L / W748S+E1143G mutants (patient derived fibroblasts), with mtDNA / nDNA normalized to undepleted vs drug concentration, for 5 and 15 days. After a ten-day depletion, both W748S+E1143G / W748S+E1143G and T251I+P587L / W748S+E1143G had a dose dependent recovery of mtDNA after 15-day or 21 -day treatment with the drug.[000184] Example 7.[000185] The purpose of this example was to evaluate l-((S)-8-chlorochroman-4-yl)-3- (2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea in a biochemical assay to determine the recovery response vs drug concentration in human fibroblasts harboring POLy mutations.[000186] A DNA synthesis assay was performed on a single-stranded DNA template using a 20-mer oligonucleotide hybridized to M13mpl8 single-stranded DNA template. Reactions were performed at a final volume of 10 pL. Each reaction contained 0.5 nM of template DNA, 25 mM Tris-HCl, pH 8.0, 1 mM TCEP, 10 mM MgC12, 0.1 mg / mL BSA, 100 pM of all four dNTPs, 0,02% Triton X-100, 200 nM mtSSB (calculated as a tetramer), 0.5 nM of the specified POLgA variants, and 0.65 nM POLgB (calculated as a dimer).Reaction mixtures were distributed into microplates (384-well) with wells containing compounds prepared from 10 mM compound stocks in 100% DMSO (final compound concentrations indicated in the figure). Equal amounts of DMSO without any compound wereAttorney Docket No. PTZ-011WOadded to positive and negative control reactions. The reactions were incubated at 37°C for 2 h in a VWR INCU-Line incubator and terminated by the addition of 10 pL of 50 mM EDTA, 0,02% TRITON X-100, and SYBR Green I (1: 5000) followed by incubation for 20 min at room temperature. The fluorescence signal was analyzed using a BMG PHERAstar microtiter plate reader (between 485-520 nm).[000187] Each compound concentration series (10 step half-log dilution) was plated in duplicates. Nonlinear regression analysis (variable slope, 4 parameters) was used for the curve fitting to determine AC50 value and max response (curve plateau) in which POLg mutant response is shown as relative to WT response.[000188] FIG. 8 shows the results of the DNA synthesis assay for l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea, with a graph of mtDNA recovery response vs drug concentration in POLy patient fibroblasts (A467T, G848S, and W748S). ACso (pM) for A467T, G848S, and W748S was 2.58, 0.438, and 0.442, respectively, and Max activation (WT ratio) for A467T, G848S, and W748S was 0.75, 0.95, and 0.65, respectively.[000189] Example 8.[000190] The purpose of this example was to evaluate the ability of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea to accelerate mtDNA recovery in a concentration-dependent manner in human fibroblasts harboring POLy mutations.[000191] Primary fibroblasts were obtained from patients with mutations in POLG (NP_001119603.1) carrying two heterozygous mutations p.[Ala467Thr];[Gly848Ser] (FIG.9A), a homozygous p.[Ala467Thr] mutation (FIG. 9B), 3 heterozygous mutations p.[Trp748Ser];[Glull43Gly]; [Arg232His] (FIG. 9C) and two heterozygous mutations p.[Gly303Arg];[Ala467Thr] (FIG. 9D). 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 EtBr to the culture medium for 7 days. On day 7, quiescence was induced by culturing the cells in EtBr-free DMEM media (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 0.1% FBS. On day 10, l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-Attorney Docket No. PTZ-011WO1 -hydroxy ethyl)thiazol-4-yl)urea was added at concentrations of 0.01, 0.03, 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.[000192] 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 (+EtBr = 7-day depletion sample).[000193] l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea accelerated mtDNA recovery in a concentration-dependent manner (FIGs. 9A-9D). Data is shown for EtBr depleted quiescent cells. Treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea over 7- or 14-days showed a dose-dependent acceleration of mtDNA recovery in quiescent A467T / G848S (FIG. 9A),W748S+E1143G / R232H (FIG. 9C), and G303R / A467T (FIG. 9D) mutant fibroblasts. In quiescent A467T / A467T fibroblasts (FIG. 9B), the DMSO control recovered to baseline within 14-days, but l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea treatment still showed a trend of increased mtDNA levels after recovery.Attorney Docket No. PTZ-011WO[000194] Example 9.[000195] The purpose of this example was to evaluate the ability of compounds described herein to increase mtDNA copy number in POLy mutants.[000196] Primary fibroblasts were obtained from patients with mutations in POLG (NP_001119603.1) carrying a homozygous p.[Ala467Thr] mutation (FIG. 10A), two heterozygous mutations p.[Ala467Thr];[Gly848Ser] (FIG. 10B), and two heterozygous mutations p.[Trp748Ser; Glul 143Gly]; [Arg232His] (FIG. 10C). 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 EtBr to the culture medium for 7 days (T7). On day 7, quiescence was induced by full confluency as well as starvation medium (DMEM with 4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 0.1% FBS without EtBr (T7+3). On day 10, l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea was added at concentration of 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.[000197] 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.Attorney Docket No. PTZ-011WO[000198] Three quiescent POLy mutant fibroblasts showed better recovery of mtDNA when treated with l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea vs control (FIGs. 10A-C, T7: 7-day depletion in proliferation phase; and T7+3: 7-day depletion in proliferation phase and 3-day recovery in quiescent phase). Data was for EtBr-depleted quiescent cells, 2 time points (7 and 14 days). FIG. 10A shows results for the mutant fibroblast A467T / A467T, with mtDNA copy number measured for undepleted, T7, T7+3, DMSO at day 7, compound (1 pM) at day 7, DMSO at day 14, and compound (1 pM) at day 14. FIG. 10B shows results for the mutant fibroblast A467T / G848S, with mtDNA copy number measured for undepleted, T7, T7+3, DMSO at day 7, compound (1 pM) at day 7, DMSO at day 14, and compound (1 pM) at day 14. FIG. 10C shows results for the mutant fibroblast W748S + El 143G / R232H, with mtDNA copy number measured for undepleted, T7, T7+3, DMSO at day 7, compound (1 pM) at day 7, DMSO at day 14, and compound (1 pM) at day 14.[000199] Example 10.[000200] The purpose of this example was to evaluate the ability of compounds described herein to accelerate mtDNA recovery in human fibroblasts harboring POLy mutations.[000201] Primary skin fibroblasts from two patients with mutations in POLG(NP_001119603.1) p.[Ala467Thr] and [Gly848Ser] (FIG. 11A) were obtained from the Swedish Biobank. 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 EtBr to the culture medium for 4 days, followed by a return to EtBr-free media. Five compounds were added at concentrations of 1, 10, and 100 nM, while vehicle (0.1% DMSO) served as a control.Treatment was performed for 5 days. mtDNA was amplified using primers specific to human CYTB gene in the mitochondrial genome, and 18S gene as nuclear reference gene. Results are calculated as mtDNA / nuclear (nDNA) and shown as normalized to vehicle control.[000202] Primary fibroblasts were obtained from patients with mutations in POLG (NP_001119603.1) carrying two heterozygous mutations p.[Ala467Thr];[Gly848Ser] (FIG.11B), two heterozygous mutations p.[Trp748Ser;p. Glul 143Gly]; [Arg232His] (FIG. 11C), and a homozygous p.[Ala467Thr] mutation (FIG. 11D). Fibroblasts were cultured in DMEMAttorney Docket No. PTZ-011WO(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 EtBr to the culture medium for 4 days. l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea was added at concentrations of 0.01, 0.03, 0.1 and 1 pM, while vehicle (0.01% DMSO) served as a control. Compound treatment was performed for 5 days in a proliferation state. All conditions were performed in triplicates.[000203] 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.[000204] FIGS. 11A-D show that l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea accelerated mtDNA recovery in human fibroblasts harboring POLy mutations. l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea exhibited dose-dependent acceleration of mtDNA recovery post EtBr depletion in POLy patient fibroblasts in both screening and small-scale validation experimental paradigms. The graphs show EtBr depleted proliferating cells, dose response. FIG. 11A shows a graph of screening data for A467T / G848S, with normalized mtDNA levels (to DMSO) vs compound concentration (pM). FIGS. 11B-D show small scale validation data. FIG. 11B shows a graph of mtDNA copy number per cell for the mutant A467T / G848S for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)ureaAttorney Docket No. PTZ-011WOat 0.01 pM, 0.03 pM, 0.1 pM, and 1 pM. FIG. 10C shows a graph of mtDNA copy number per cell for the mutant W748S + El 143G / R23H for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea at 0.01 pM, 0.03 pM, 0.1 pM, and 1 pM. FIG. 11D shows a graph of mtDNA copy number per cell for the mutant A467T / A467T for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.01 pM, 0.03 pM, 0.1 pM, and 1 pM.[000205] Primary fibroblasts were obtained from patients with mutations in POLG identified in Table 7 below. Using similar methods as described in this Example, each patient derived fibroblast cell line with POLG mutations was treated with [XX] pM of the indicated compound. Table 7 summarizes the ability of the tested compounds in improving mtDNA recovery compared to control(DMSO). 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 ”VH His Compound 14 (C14). (5)-6-(3-(8-chlorochroman- 4-yl)ureido)-N-methylpicolinamide is Compound 15 (Cl 5).Table 7. Ability of tested compounds to improve mtDNA recoveryPrimary fibroblastPOLG mutations C8 C7 C6 C9 CIO C14 C13 C15 C12 POLG W748S+E1143G / W748S+E1143G A A APOLG T251I+P587L / W748S+E1143G A A A APOLG W748S+E1143G / M1163R A APOLG A467T / R574W A APOLG G737R / R232H #1 A APOLG G737R / R232H #2 A APOLG F197S / T914P C CPOLG G303 / A467T A A AAttorney Docket No. PTZ-011WOPOLGY955C A A A APOLGY955HPOLG A467T / G848S A A A A A A POLG W748S+E1143G / R232H A A A A A A POLG A467T / A467T A B B A CPOLG A467T / G848S A APOLG W748S+E1143G / R232H A APOLG A467T / A467T A AA: p<0.05; B: p >0.05 but < 0.1, C: p>0.1.[000206] This example shows compounds disclosed here increase mtDNA levels in cells with a variety of PMD and MDDS-related POLG mutations.[000207] Example 11.[000208] The purpose of this example was to evaluate the ability of compounds described herein to accelerate mtDNA recovery in human fibroblasts harboring POLy mutations.[000209] Primary fibroblasts were obtained from patients with mutations in POLG (NP_001119603.1) carrying two recessive heterozygous mutations p.[Gly737Arg];[Arg232His] (FIGs. 12A-B), and a patient carrying two heterozygous mutations p.[Phel97Ser];[Thr914Pro] (FIG. 12C). 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 EtBr to the culture medium for either 7 days (G737R / R232H) or 11 days (F197S / T914P). After EtBr depletion (day 7 or 11), quiescence was induced by culturing the cells in EtBr-free DMEM media (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) supplemented with 0.1% FBS. 3 days after quiescence induction (day 10 or 14), 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea was 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.Attorney Docket No. PTZ-011WO[000210] 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 (+EtBr = 7-day (A& B) / 11-day (C) depletion sample).[000211] l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea accelerated mtDNA recovery in quiescent POLy and RRM2B mutant fibroblasts (FIGs. 12A-C). The graphs of FIGs. 12A-C show EtBr depleted, quiescent fibroblasts at 2 time points (7 and 14 days). Collectively, the data shows that quiescent or non-mitotic conditions exacerbate mtDNA recovery phenotypes in patient fibroblasts. FIG.12A shows a graph of mtDNA copy number per cell for the mutant POLy G737R / R232H fibroblasts for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 0.1 pM (7 days), 1 pM (7 days), 0.1 pM (14 days, and 1 pM (14 days). FIG.12B shows a graph of mtDNA copy number per cell for the mutant POLy G737R / R232H fibroblasts for each of non-depleted, +EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea at 0.1 pM (7 days), 1 pM (7 days), 0.1 pM (14 days, and 1 pM (14 days) (repeat of the experiment for FIG 9A). FIG. 12C shows a graph of mtDNA copy number per cell for the mutant POLy F197S / T914P fibroblasts for each of non-depleted,Attorney Docket No. PTZ-011WO+EtBr, DMSO, and l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea at 1 pM (7 days), and 1 pM (14 days).[000212] Example 12.[000213] The purpose of this example was to evaluate the ability of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea to increase mtDNA copy number in various differentiated POLy mutant DE cells.[000214] A WT iPSC line (PGP1; Synthego), an isogenic iPSC line carrying the POLG mutation A467T / A467T (introduced by genome editing into the PGP1 WT line; S-A467T / A467T), and iPSC lines reprogrammed from patient fibroblasts carrying the A467T / A467T mutation (R-A467T / A467T) or the W748S / W748S mutation (R-W748S / W748S), respectively, were differentiated into Definitive Endoderm (DE) using the Cellartis DE Differentiation kit (Cat.no. Y30035, Takara Bio) according to the user manual. On day 0, iPSC from the WT and the S-A467T / A467T cell lines were seeded at a density of 5 x 104cells / cm2, and iPSC from the R-A467T / A467T and R-W748S / W748S lines were seeded at a density of 5 x 104and 7 x 104cells / cm2. The mutant iPSC lines were treated with either a DMSO vehicle control (0.01%) or 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea (two 12-wells per condition). WT iPSC were only treated with DMSO vehicle. Medium changes were performed on days 1, 2, 3, 4 and 6 of differentiation with medium supplemented with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea or DMSO as described above. On days 3, 4, and 6, the medium was supplemented in addition with 10 nM 5-aza-2 deoxy cytidine for all cell lines and treatment groups. On day 7 of differentiation, DE cell pellets were collected from two individual wells per treatment. Cell pellets were stored at -80°C until DNA extraction and mtDNA copy number determination by qPCR as described under 14 A.[000215] l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea increases mtDNA copy number in various differentiated POLy mutant DE cells (S-A467T / A467T, R-A467T / A467T, R-W748S / W748S, and WT, FIG. 13). The graphs depict mtDNA copy number vs DMSO and 1 pm l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea for each of the different mutant cell types and WT.Attorney Docket No. PTZ-011WO[000216] Example 13.[000217] The purpose of this example was to evaluate the ability of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea to increase mtDNA in human iPSCs and definitive endoderm.[000218] Human induced pluripotent stem cell lines (iPSC) carrying the POLG mutations G848S / G848S (14A) or A467T / A467T (14B) were cultured in the Cellartis DEF-CS culture system in a 37°C humidified incubator with 5% CO2 according to the manufacturer’s user manual (Cat.no. Y30010, Takara Bio). The POLG mutations were introduced by genome editing into a WT line (PGP1; Synthego).[000219] For assessing the effect of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea on mtDNA copy number in these iPSC lines, iPSC were expanded and at the beginning of the study (on day 0) seeded into 24-well plates at a density of 1 x 105cells / cm2(G848S / G848S ) or 0.9 x 105cells / cm2(A467T / A467T ) in 1 ml medium / 24-well. Cells were treated with 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea, 0.1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea or 0.01% DMSO vehicle for 120 h (day 0 to 5). Per condition and cell line, three 24-wells were seeded. Medium changes were performed on day 1, 2, and 4 after start of the treatment with medium supplemented with 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea, 0.1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea or 0.01% DMSO. On day 0 and on day 5 (after 120 hr of treatment initiation), cell pellets with 1 x 105cells were collected from 3 individual wells per cell line and treatment. Cell pellets were stored at -80°C until DNA extraction and mtDNA copy number determination by qPCR. DNA samples were extracted from cell pellets with the Zymo Genomic DNA Clean & Concentrator- 10 kit and EZ-Vac Vacuum Manifold. 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 reference gene. For quantitativeAttorney Docket No. PTZ-011WOassessment 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 plasmid contains CYTB + B2M, 244 base pair (bp) insert into pEX-A128 vector (backbone size is 2450 bp) and the total size is 2694 bp.[000220] l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea increased mtDNA in human iPSCs and definitive endoderm (FIGs 14A-D). 5-day treatment of 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea significantly increased mtDNA level in G848S / G848S (FIG. 14A) and A467T / A467T iPSCs (FIG. 14C). 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea restored mtDNA levels to WT levels during definitive endoderm differentiation (DE) towards hepatocytes (FIG. 14B). Combination treatment of 1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea and standard supplements increased %cell number and restores defective DE differentiation in mutant A467T / A467T iPSCs to wild-type levels (FIG. 14D)[000221] Example 14.[000222] The purpose of this example was to evaluate the ability of compounds described herein to rescue a respiration deficiency present in human fibroblasts harboring POLy mutations.[000223] Neural stem cells (NSCs) with wildtype genotype (WT) or harbouring a homozygous G848S mutation (G848S / G848S) were cultured in triplicates per treatment condition on Matrigel-coated 6-well plates in neural progenitor medium and passaged using Accutase® when they reached 90-95% confluency. At days 1, 3 and 5, 0.01% DMSO was added to the medium of 3 separate wells of mutant cells, and on Day 10 a Mito stress test using the Agilent Metabolic flux analyzer was performed (FIG. 15A).[000224] Neural stem cells (NSCs) harbouring a homozygous G848S mutation (G848S / G848S) were cultured for 5 days in triplicates per treatment condition on Matrigel-coated 6-well plates in neural progenitor medium containing either 0.01% DMSO, 1 pM or 3 pM of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea (FIGs. 15B-C).Attorney Docket No. PTZ-011WO[000225] On the day before the experiment, an XFe96 Pro cartridge was hydrated with 200 pL of calibrant solution per well and incubated at 37 °C overnight. The cells were seeded in 8 technical replicates at 3xl04cells / well in Neural progenitor medium into a pre-coated Seahorse XFe96 Pro Cell Culture Microplate. The plate was then incubated in a CO2 incubator at 37 °C overnight to allow the cells to adhere and equilibrate. The next morning, growth media was exchanged with Seahorse Phenol Red-free DMEM supplemented with 5 mM glucose, 2 mM glutamine and 1 mM sodium-pyruvate and the cells were incubated for Ih at 37 °C to equilibrate in the Seahorse medium. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were measured using the XF Cell Mito stress test according to the manufacturer’s instructions. Namely, the mitochondrial inhibitors oligomycin A and rotenone / antimycin A as well as the uncoupler FCCP were diluted according to the manual in Seahorse medium to the following final concentrations: oligomycin 1.5 pM, FCCP 2 pM, rotenone / antimycin 0.5 pM. 20, 22 and 24 pL of those were loaded into the respective ports on the cartridge just before calibration of the Seahorse analyzer and subsequent analysis of the prepared cell plate. Upon completion of the Seahorse assay, all medium was removed from the plate and the plate was frozen at -80 °C overnight. For cell quantification, this plate was thawed and the CyQuant (Thermo Fisher #C7026) assay was performed. For the assay, lysis buffer was diluted 1:20 in water and supplemented with 1:400 CyQuant dye. 200 pL of this mixture was added to each well before the plate was incubated for 5 min, protected from light. Fluorescence was measured in a BG Labtech Spectrostar plate reader and cell number was quantified using a cell standard curve. Data analysis and normalization was performed using the Agilent Wave software and Prism 10.0.[000226] G848S / G848S NSCs have a respiration deficiency, which was rescued by 1- ((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea (FIGs. 15A-C). G848S / G848S homozygous cell line is respiration deficient over the 10-day time course. No dose response was observed between 1 & 3 pM compound (the timepoints were similar, OCR = oxygen consumption rate = oxygen flux; ECAR = extracellular acidification rate = proton flux). FIG. 15A shows that G848S / G848S NSCs have a respiratory deficit when compared to WT NSCs, with the graph depicting OCR (pmol O2 / min / 103cells vs time (minutes) (5, 7 and 10 days), for DMSO and WT. FIGs. 15B and 15C show that improvements in cellularAttorney Docket No. PTZ-011WOenergetics were observed by 5-days of treatment with the compound, with FIG. 15B showing the oxygen consumption rate at day 5 (OCR (pmol O2 / min / 103cells) vs time (minutes), for DMSO and compound at 1 and 3 pM, and FIG. 15C showing the extracellular acidification rate at day 5 of treatment with the compound (ECAR (mpH / min / 103cells) vs time (minutes), for DMSO and compound at 1 and 3 pM.[000227] Example 15.[000228] The purpose of this example was to evaluate the ability of compounds described herein to rescue a respiration deficiency present in human fibroblasts harboring POLy mutations.[000229] Wildtype neural stem cells (NSCs) or NSCs harbouring a homozygous G848S mutation (G848S / G848S) were cultured for 7 days in triplicates per treatment condition on Matrigel-coated 6-well plates in neural progenitor medium containing either 0.01% DMSO, or 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM or 1 pM of l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea (FIGs. 16A-C). While some of the cells were used to run the Seahorse assay (FIGs. 16A-B), the rest of the cells were pelleted and frozen down for mtDNA analysis (FIG. 16C).[000230] On the day before the experiment, an XFe96 Pro cartridge was hydrated with 200 pL of calibrant solution per well and incubated at 37 °C overnight. The cells were seeded in 8 technical replicates at 3xl04cells / well in Neural progenitor medium into a pre-coated Seahorse XFe96 Pro Cell Culture Microplate. The plate was then incubated in a CO2 incubator at 37 °C overnight to allow the cells to adhere and equilibrate. The next morning, growth media was exchanged with Seahorse Phenol Red-free DMEM supplemented with 5 mM glucose, 2 mM glutamine and 1 mM sodium-pyruvate and the cells were incubated for Ih at 37 °C to equilibrate in the Seahorse medium. OCR (including basal and maximal respiration, allowing for the calculation of ATP production) and ECAR were measured using the XF Cell Mito stress test according to the manufacturer’s instructions. Namely, the mitochondrial inhibitors oligomycin A and rotenone / antimycin A as well as the uncoupler FCCP were diluted according to the manual in Seahorse medium to the following final concentrations: oligomycin 1.5 pM, FCCP 2 pM, rotenone / antimycin 0.5 pM. 20, 22 and 24 pL of those were loaded into the respective ports on the cartridge just before calibration ofAttorney Docket No. PTZ-011WOthe Seahorse analyzer and subsequent analysis of the prepared cell plate. Upon completion of the Seahorse assay, all medium was removed from the plate and the plate was frozen at -80 °C overnight. For cell quantification, this plate was thawed and the CyQuant (Thermo Fisher #C7026) assay was performed. For this, lysis buffer was diluted 1:20 in water and supplemented with 1:400 CyQuant dye. 200 pL of this mixture was added to each well, before the plate was incubated for 5 min protected from light. Fluorescence was measured in a BG Labtech Spectrostar plate reader and cell number quantified using a cell standard curve. Data analysis and normalization was performed using the Agilent Wave software and Prism 10.0.[000231] For the mtDNA analysis, Cell pellets were stored at -80°C until DNA extraction and mtDNA copy number determination by qPCR. DNA samples were extracted from cell pellets with the Zymo Genomic DNA Clean & Concentrator- 10 kit and EZ-Vac Vacuum Manifold according to manufacturer’s instructions. 10-20 ng DNA were then transferred in triplicates onto a 384 well plate and 8 ul PCR mastermix was added (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 18S gene as nuclear reference gene. The relative amount of mtDNA compared to nuclear DNA was calculated using the 2 ddCt method and statistics were calculated using the Prism 10.0 software.[000232] l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea increased mtDNA and basal respiration in G848S / G848S NSCs (FIGs. 16A-C). 1 pM 1-((S)-8-chlorochroman-4-yl)-3 -(2-((S)- 1 -hydroxy ethyl)thiazol-4-yl)urea treatment improved respiration after 7 days, and results were consistent with 10-day treatment. Lower concentrations showed improvements in cell morphology but no significant respiratory improvement. Compound-treated NSCs demonstrated improvements in cellular energetics, following 7-days of treatment. FIG. 16A shows a graph of oxygen consumption rate - day 7, with OCR (pmol / min / 104cells) vs time (minutes) for each of WT, DMSO, 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM, and 1 pM of the compound. FIG. 16B shows the basal respiration 7 day, with OCR (pmol / min / 104cells) for each of WT, DMSO, 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM, and 1 pM of the compound. FIG. 16C shows that compound-Attorney Docket No. PTZ-011WOtreated NSCs have higher mtDNA, with the graph depicting mtDNA 7-day, with mtDNA level (normalized to WT) for each of WT, DMSO, 0.05 pM, 0.1 pM, 0.25 pM, 0.5 pM, 0.75 pM, and 1 pM of compound. This data demonstrates that G848S / G848S NSCs have a respiration deficiency, which can be rescued by the compounds described herein (e.g., 1 -((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea).[000233] Example 16.[000234] The purpose of this example was to evaluate the ability of compounds described herein to enhance cellular respiration for human fibroblasts harboring POLy mutations.[000235] Wildtype neural stem cells (NSCs) or NSCs harbouring a homozygous G848S mutation (G848S) were cultured for 10 days on Matrigel-coated 6-well plates in neural progenitor medium containing either 0.01% DMSO, 0.1 pM, or 1 pM of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea (FIGs. 17A-B).[000236] On the day before the experiment, an XFe96 Pro cartridge was hydrated with 200 pL of calibrant solution per well and incubated at 37 °C overnight. The next day, cells were seeded at 6xl04cells / well in neural progenitor medium into a pre-coated Seahorse XFe96 Pro Cell Culture Microplate. The plate was then incubated in a CO2 incubator at 37°C for 4h to allow the cells to adhere and equilibrate. Next, growth media was exchanged with Seahorse Phenol Red-free DMEM supplemented with 5 mM glucose, 2 mM glutamine and 1 mM sodium-pyruvate and the cells were incubated for Ih at 37°C to equilibrate in the Seahorse medium. OCR (including basal and maximal respiration, allowing for the calculation of ATP production) and ECAR were measured using the XF Cell Mito stress test according to the manufacturer’s instructions. Namely, the mitochondrial inhibitors oligomycin A and rotenone / antimycin A as well as the uncoupler FCCP were diluted according to the manual in Seahorse medium to the following final concentrations: oligomycin 1.5 pM, FCCP 2 pM, rotenone / antimycin 0.5 pM. 20, 22 and 24 pL of those were loaded into the respective ports on the cartridge just before calibration of the Seahorse analyzer and subsequent analysis of the prepared cell plate. Finally, DAPI dye was loaded into the fourth port of the cartridge. After the Mito stress test was completed, DAPI was injected by the Metabolic flux analyzer into the wells staining the cells. The plate was thenAttorney Docket No. PTZ-011WOimaged and cell number quantified for normalization of this plate. Data analysis and normalization was performed using the Agilent Wave software and Prism 10.0.[000237] l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea enhanced cellular respiration (FIG. 17A-B). POLG G848S mutant neural stem cells treated with l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea increased basal and ATP -Linked oxidative phosphorylation, with improved cellular respiration (FIG.17A = basal respiration) and energy production (FIG. 17B= ATP production rate) following l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea treatment.[000238] Example 17.[000239] The purpose of this example was to evaluate the ability of compounds described herein to enhance cellular respiration for human fibroblasts harboring POLy mutations.[000240] Primary fibroblasts were obtained from patients with mutations in POLG (NP_001119603.1) carrying two heterozygous mutations p.[Ala467Thr];[Gly848Ser] (FIG.18A) and 3 heterozygous mutations p.[Trp748Ser];[Glul 143Gly]; [Arg232His] (FIG. 18B).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 EtBr to the culture medium for 4 days. On day 5, cells were cultured in EtBr-free DMEM media (4.5 g / L glucose, 4 mM glutamine, 110 mg / L sodium pyruvate) and (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea was added at a concentration of 1 pM, while vehicle (0.01% DMSO = blue) 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. 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. Each datapoint represents three biological samples and error bars indicate standard deviations.Attorney Docket No. PTZ-011WO[000241] PolG patient fibroblasts were depleted of mtDNA as described above and cultured in the presence of 0.01% DMSO or 1 pM (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea for 7 days. Cells were split every 3 days. On the day before the experiment, an XFe96 Pro cartridge was hydrated with 200 pL of calibrant solution per well and incubated at 37 °C overnight. On the day of the experiment, the cells were seeded at 2xl04cells / well in normal growth media (DMEM) in a pre-coated Seahorse XFe96 Pro Cell Culture Microplate. The plate was then incubated in a CO2 incubator at 37 °C for 2h to allow the cells to adhere. Next, growth media was exchanged with Seahorse Phenol Red-free DMEM supplemented with 5 mM glucose, 2 mM glutamine and 1 mM sodium-pyruvate and the cells were incubated for Ih at 37 °C to equilibrate in the Seahorse medium. OCR (including basal and maximal respiration, allowing for the calculation of ATP production) and ECAR were measured using the XF Cell Mito stress test (Agilent, Cat#) according to the manufacturer’s instructions. Namely, the mitochondrial inhibitors oligomycin A and rotenone / antimycin A as well as the uncoupler FCCP were diluted according to the manual in Seahorse medium to the following final concentrations: oligomycin 1 pM, FCCP 2 pM, rotenone / antimycin 0.5 pM. 20, 22 and 24 pL of those were loaded into the respective ports on the cartridge just before calibration of the Seahorse analyzer and subsequent analysis of the prepared cell plate. Upon completion of the Seahorse assay, all medium was removed from the plate and the plate was frozen at -80 °C overnight. For cell quantification, this plate was thawed and the CyQuant (Thermo Fisher #C7026) assay performed. For the assay, lysis buffer was diluted 1:20 in water and supplemented with 1:400 CyQuant dye. 200 pL of this mixture was added to each well, before the plate was incubated for 5 min protected from light. Fluorescence was measured in a BG Labtech Spectrostar plate reader and cell number quantified using a cell standard curve. Data analysis and normalization was performed using the Agilent Wave software and Prism 10.0.[000242] (S)-l -(8-chlorochroman-4-yl)-3-(l -phenyl- lH-pyrazol-3-yl)urea enhanced cellular respiration (i.e., increased in mtDNA and respiration in POLy patient fibroblasts). FIGS. 18A & B show that (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea improved mtDNA recovery following depletion. FIG. 18A shows that for mutant A467 / G848S patient fibroblasts, (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea produced a significant increase in mtDNA levels, demonstrating mtDNAAttorney Docket No. PTZ-011WOrecovery following depletion. FIG. 18B shows similar results for the mutant W748S / R232H patient fibroblasts. FIGS. 18C & D show that (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea increased cellular respiration for the A467 / G848S and W748S / R232H mutant patient fibroblasts, including both basal respiration (FIG. 18C) and maximal respiration (FIG. 18D). FIG. 18E shows that (S)-l-(8-chlorochroman-4-yl)-3-(l-phenyl-lH-pyrazol-3-yl)urea shifted ATP production rate to favor OXPHOS, for the A467 / G848S and W748S / R232H mutant patient fibroblasts.[000243] Example 18.[000244] The purpose of this example was to evaluate the ability of compounds described herein to support differentiation of POLy cells from iPSCs to hepatocytes.[000245] An iPSC line carrying the POLG mutation G848S / G848S (introduced by genome editing into the PGP1 WT line; S-G848S / G848S) was differentiated into Definitive Endoderm (DE) using the Cellartis DE Differentiation kit (Cat.no. Y30035, Takara Bio) according to the user manual. S-G848S / G848S iPSC were seeded at a density of 1 x 105cells / cm2on day 0 and were either untreated (FIG. 19A) or treated with 0.1 pM l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea (FIG. 19B). Medium changes were performed on days 1, 2, 3, 4 and 6 of differentiation with medium supplemented as described above. On day 7 of differentiation, the cell culture morphology was assessed, and representative micrographs were taken of untreated (FIG. 19A) or compound-treated (FIG. 19B) DE cultures.[000246] FIGS. 19A & B show brightfield images of representative S-G848S / G848S induced pluripotent stem cells (iPSCs). Treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l -hydroxy ethyl)thiazol-4-yl)urea supported differentiation of POLy cells from iPSCs to hepatocytes (i.e., treatment with l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea improved iPSC viability and cellular morphology). FIG. 19A shows S-G848S / G848S control, with low viability and poor cellular morphology; hepatocyte differentiation was not viable. FIG. 19B shows S-G848S / G848S + 100 nM compound, where cell viability was greatly improved, and l-((S)-8-chlorochroman-4-yl)-3-(2-((S)-l-hydroxyethyl)thiazol-4-yl)urea appeared to recover hepatocyte differentiation potential.[000247] Example 19.Attorney Docket No. PTZ-011WO[000248] 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 in Patients with Primary Mitochondrial Disease Associated with Pathogenic POLG Mutations.[000249] Number to be enrolled: Up to 20 adolescent / adult patients with primary mitochondrial disease.[000250] Objectives: Primary Objective: Safety- to assess the safety and tolerability of 1-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea 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.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 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; (ii) Plasma PK parameters including but not limited to Tmax, Cmax, volume of distribution, area under the curve (AUC) and T1 / 2.[000251] Secondary Objectives: Pharmacodynamics- to assess the effects of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea 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 and FGF-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.).Attorney Docket No. PTZ-011WO[000252] Exploratory Objectives: (1) To evaluate change from baseline in exploratory biomarkers related to mitochondrial disease including but not limited to circulating cell-free mtDNA (ccf mtDNA); (2) To evaluate change from baseline in clinical assessments of myopathy including but not limited to 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); (3) To evaluate change from baseline in sensorineural hearing (Beecher 2024 PMM ref); (4) To evaluate change from baseline in clinical / EEG assessments of neuropathology; and (5) To evaluate presence and PK of potential l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l-hydroxyethyl)thiazol-4-yl)urea metabolites in plasma samples.[000253] Study Design: l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea is a Ph2a, first in patient, open-label, randomized, two dose level study of l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea in adolescent / adults patients with primary mitochondrial disease (PMD) and pathogenic polymerase gamma (POLG) mutations. l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea is a novel, orally administered small molecule developed for systemic distribution that is anticipated to increase mtDNA copy number via acceleration of the mitochondrial DNA polymerase (POLy).[000254] The integrated study design will enroll adolescent and adult patients with pathogenic mutations of POLG presenting with symptoms consistent of POLG disease. Symptom-specific analysis will be conducted based on the disease presentation such as POLG-myopathy or POLG-CNS clinical pathology. The heterogeneous nature of POLG disease presentation leads to the need for patient-specific outcome analysis based on disease presentation.[000255] The Ph2a first-in-patient study incorporated a dose escalation and an age de-escalation design. Based on preclinical results and dose modeling, two l-((S)-8-chlorochroman-4-yl)-3-(2-((R)-l -hydroxy ethyl)thiazol-4-yl)urea dose levels will be tested with BID daily dosing over 12 weeks followed by a 12 week recovery period. Both males and females will be eligible to participate.Attorney Docket No. PTZ-011WO[000256] For each cohort, potential subjects will be screened a maximum of 28 days (Day -28) prior to Check-in (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 systemic markers of mitochondrial dysfunction (two values, at least 1 week apart), and in patients presenting with lower-limb myopathy, a muscle biopsy for assessing muscle mtDNA copy number prior to intervention.[000257] Subjects will be admitted to the clinical unit on Day -1 for pre-dosing testing as described in the SoA. No more than 2 subjects will start dosing on the same day. On the morning of Day 1, subjects will receive a test dose of study drug (low or high dose depending on their cohort) in a fasted state (at least 10 hours pre-dose and 4 hours post-dose). Assuming Day 1 dosing is well tolerated, subjects will continue qD dosing through D3 (48 hrs post first dose) while remaining at the Phase 1 unit for safety monitoring and collection of blood samples for PK analysis / safety assessments / PD markers / expl oratory analyses. Duration of domiciling may be extended if there is a safety concern.[000258] Assuming no clinically-concerning adverse events as determined by the site Investigator, sub...

Claims

Attorney Docket No. PTZ-011WOWHAT IS CLAIMED IS:

1. A method of treating a Mitochondrial DNA Depletion Syndrome (MDDS) in a subject in need thereof, the method comprising:optionally identifying a subject diagnosed with, or at a risk of developing, a MDDS; andadministering 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 has one or more mutations or deletions 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.

3. The method of claim 2, wherein the subject has one or more mutations or deletions in the POLG gene.

4. The method of claim 2 or 3, wherein the method optionally comprises identifying a subject diagnosed with or at risk of developing a PMD.

5. The method of claim 1 or 4, wherein the subject at risk of developing a PMD of MDDS has one of more symptoms of having a mutation in the POLG gene.

6. The method of claim 5, wherein the symptom is neurological, ophthalmological, gastrointestinal, endocrinological, myopathy, or hepatopathy.

7. The method of claim 6, wherein:the neurological symptom is a seizure (focal, myoclonic, epilepsia partialis continua, convulsive status epilepticus), ataxia, peripheral neuropathy, or sensorineural hearing loss,the ophthalmological symptom is ptosis, nystagmus, progressive externalAttorney Docket No. PTZ-011WOophthalmoplegia, cataract, cortical blindness, or pigmentary retinopathy,the gastrointestinal symptom is a feeding difficulty, chronic diarrhea, or vomiting,the endocrinological symptom is diabetes mellitus type 1, diabetes mellitus type 2, or adrenal insufficiency,the myopathy symptom is muscle weakness, myalgia, muscle fatigue, muscle stiffness, orthe hepatopathy symptom is liver failure (acute, chronic, or recurrent), cholestasis, liver fibrosis, or elevated transaminases.

8. The method of claim 6, wherein the neurological symptom is a seizure (focal, myoclonic, epilepsia partialis continua, convulsive status epilepticus).

9. The method of claim 6, wherein the neurological symptom is ataxia.

10. The method of claim 6, wherein the hepatopathy symptom is liver failure.

11. The method of claim 1 or 4, wherein identifying a subject diagnosed with, or at risk of developing a PMD or MDDS comprises diagnosing the subject by sequencing the subject’s POLG gene.

12. The method of claim 1, 3, or 11, wherein POLG gene mutation comprises, or the sequence of the subject’s POLG gene comprises, one or more mutations in the POLG gene selected from the group consisting of: R3P, S28C, G1 ID, Q43R, Q45R, Q49E, Q68X, A(CAG)n, S64L, L79F, L83P, H110Y, P116Q, D122Y, D136E, A143V, P163S, R193Q, C224Y, R227P, R227W, R232G, R232H, W235X, P241L, L244P, T251I, G268A, R275X, R275Q, H277L, Y282D, G303R, L304R, S305R, Q308H, R309L, R309H,-W312R, K319E, P324S, T326fs61X, T326fs387X, W347_L356del, W347fs356X, E358A, R374X, G380D, E386H, R386C, L392V, L392W, R417T, R417X, C418R, L424Gfs28X, L424X, G426S, L428P, G426S, M430L, G431V, S433C, M340L, G431V, S433C, Q449X, T452X, Y452X, L463F, M464T, A467T, N468D, Q497H, K498T, S511N, K512M, G517V, R546C, K561M, R562Q, H569Q, R574W, R579W, W585X, P587L, G588D, P589L, L591F, R597W, K601E, M603L,Attorney Docket No. PTZ-011WOL605R, R617C, G621D, L623W, P625R, R627W, R627Q, R628Q, P648R, E662K, R709X, Q715X, R722H, N736S, G737R, G746S, W748S, F749S, L752P, H754Q, K755E, G763R, P765T, A767D, K768E, G785fs21X, R790H, M797del, A804T, R807P, R807C, R807H, Y831C, G848S, T849X, T849H, T851A, R852C, R852H, R853Q, R853W, V855A, V855L, A862T, N864S, R869Q, E873X, Q879H, T885S, L886P, G888S, G888D, A889T, D890A, E895G, F907I, T914P, T914A, W918R, M919T, G923D, K925fsX, K925Rfs42X, D930N, H932Y, S933R, R943H, R943C, H945L, K947R, Y951N, R953C, Y955C, A957S, A957P, A957V, F961S, A962T, R964C, L965X, L966R, G975X, Y995C, S998L, W1020X, Q1024X, V1044A, R1047Q, R1047W, K1050X, G1051R, G1052S, G1052D, E1054fs, P1073L, G1076V, C1077G, I1079L, S1080T, SI 0801, R1081P, R1091Q, S1095G, S1095R, R1096C, R1096H, SI 104C, SI 104F, Al 105T, VI 1061, Hl 110Y, LI 113P, R1128H, Hl 134R, El 136K, R1138C, R1142W, El 143G, El 145G, DI 145GfsX9, R1146C, Q1154R, M1163R, Fl 1641, L1173fsX, SI 176L, DI 184N, DI 184L, I1185T, R1187W, C1188R, K1191N, K1191R, D1196N, T1199X, G1205A, Y1210fs6X, Q1214X, Y1210fsl216X, S1230F, Q1236H, X1240Q / Y + 35aa, and any combination thereof.

13. The method of claim 12, wherein the one or more mutations is R232H, R309C, A467T, W748S, G848S, Y955C, E1143G, T251I-P987L, A467T and G484S, W748S + El 143G and R232H, G303R and A467T, G737R and R232H, F197S and T914P, A467T and R574W, Y955C, T251I and P587L, W748S and El 143G, or any combination thereof.

14. The method of claim 12 or 13, wherein the one or more mutations is A467T, W748S, G848S, R232H, and any combination thereof.

15. The method of claim 1 or 3, wherein the POLG mutation results in one or more of: mitochondrial DNA (mtDNA) deletions, reduced mtDNA levels, a reduction in mtDNA POLy polymerase activity, low processivity of the POLy polymerase, a defect in the mtDNA-binding function of the POLy polymerase, a decrease in the mtDNA- binding affinity of the POLy polymerase, or any combination thereof.Attorney Docket No. PTZ-011WO16. The method of claim 1 or 3, wherein the POLG mutation results in lower levels of mtDNA copy number in a tissue specific cell type of the subject compared to the tissue specific cell type in a subject who does not have a POLG mutation.

17. The method of claim 16, wherein the tissue specific cell type is selected from the group consisting of a fibroblast, hepatocyte, neuronal, and muscle.

18. The method of any one of claims 1 -3, 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 healthy mtDNA in the subj ect;(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 mitochondrial DNA (mtDNA) production in the subject;(e) results in an increase in mitochondrial DNA (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) improves the processivity of a POLy protein in the subject; (i) increases cellular respiration in the subject;(j) shifts ATP production rate to favor oxidative phosphorylation in the subject;(k) results in improved liver health for the subject; or(l) any combination thereof.

19. The method of claim 18, wherein the increase in the mtDNA copy number per cell is 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 aboutAttorney Docket No. PTZ-011WO45%, 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’s cell prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

20. The method of claim 18, wherein the improvement of the processivity of the POLy protein is 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 protein prior to administration of the compound of Table 1, Table 2, Table 3, Table 4, or Table 5, or a pharmaceutically acceptable salt thereof.

21. The method of any one of claims 1-3, wherein the MDDS or PMD is selected from the group consisting of Alpers-Huttenlocher syndrome (AHS), autosomal dominant progressive external ophthalmoplegia (adPEO), autosomal recessive progressive external ophthalmoplegia (arPEO), myocerebrohepatopathy spectrum (MCHS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), ataxia neuropathy spectrum (ANS), mitochondrial recessive ataxia syndrome (MIRAS), progressive external ophthalmoplegia (PEO), mitochondrial encephalomyopathy (MELAS), mitochondrial neurogastrointestinal encephalopathy (MNGIE), sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO), and spinocerebellar ataxia with epilepsy (SCAE).

22. The method of claim 21 wherein:(a) the MDDS or PMD is ataxia neuropathy spectrum (ANS) and the POLG mutation is W748S;(b) the MDDS or PMD is Alpers-Huttenlocher syndrome, myoclonic epilepsy myopathy sensory ataxia, Ataxia neuropathy spectrum or sensory ataxia neuropathy dysarthria and ophthalmoplegia and the POLG mutation is A467T;(c) the MDDS or PMD is AHS and the POLG mutation is Gly848, G848S,Attorney Docket No. PTZ-011WOT851A, R852C, R853Q, or any combination thereof;(d) the MDDS or PMD is AHS and the POLG mutation is G1 ID, Q68X, L79F, L83P, A143V, C224Y, R227P, R227W, R232G, R232H, W235X, L244P, T251I, H277L, Y282D, G303R, L304R, S305R, R309H, T326fs387X, W347fs356X, E358A, R374X, E386H, R417T, R417X, C418R, L424X, G426S, L428P, A467T, G517V, K561M, H569Q, R574W, P587L, P589L, L605R, P625R, R627Q, Q715X, R722H, G737R, W748S, F749S, L752P, H754Q, A767D, R790H, M797del, R807H, G848S, T849X, T851A, R852C, R852H, R853Q, V855L, E873X, Q879H, T885S, L886P, G888S, G888D, E895G, T914P, T914A, K925fsX, D930N, R943C, A957P, A957V, L966R, G975X, W1020X, Q1024X, V1044A, R1047W, K1050X, P1073L, C1077G, SI 0801, R1091Q, S1095R, R1096C, R1096H, Hl HOY, L1113P, H1134R, El 136K, El 143G, DI 145GfsX9, Ml 163R, LI 173fsX, Il 185T, R1187W, Cl 188R, K1191N, K1191R, Y1210fsl216X, and any combination thereof;(e) the MDDS or PMD is PEO and the POLG mutation is T25 II and P587L amino acid substitutions and / or Y955C;(f) the MDDS or PMD is autosomal dominant PEO and the POLG mutation is S511N, G293D, S933R, R943C, R943H, H945L, K947R, R953C, Y955C, A957S, F961S, I1079L, S1095R, A1105T, and any combination thereof;(g) the MDDS or PMD is autosomal recessive PEO and the POLG mutation is R3P, S28C, T2511, R275X, R275Q, L304R, Q308H, R309L, K319E, R386C, M430L, L463F, A467T, N468D, G517V, R574W, P587L, R597W, M603L, R627W, P648R, R722H, G737R, G746S, G763R, c.2354Gins, G848S, R853W, A862T, N864S, R869Q, W918R, M919T, H932Y, S998L, R1047W, G1051R, R1081P, VI 1061, R1138C, Fl 1641, SI 176L, DI 184L, DI 184N, KI 191N, T1199X, Q1214X, X1240Q / Y + 35aa, and any combination thereof;(h) the MDDS or PMD is sporadic PEO and the POLG mutation is P163S, R227W, G268A, W312R, G380D, L424X, G431V, S433C, Y452X, R562Q, R579W, W585X, R709X, R807P, A889T, R1047Q, G1076V, R1096C, S1104F, S1104C, and any combination thereof; or(i) the MDDS or PMD is ataxia neuropathy syndrome (ANS), MIRAS, SANDO, or SCAE and the POLG mutation is G1 ID, D122Y, L304R, G426S,Attorney Docket No. PTZ-011WOM464T, A467T, Q497H, L591F, K601E, R627Q, R627W, P648R, N736S, W748S, G763R, P765T, K768E, R807C, A862T, R869Q, Y951N, A962T, R964C, L965X, S1080T, El 143G, and any combination thereof.

23. The method of claim 21 or 22, wherein the MDDS or PMD is Alpers-Huttenlocher syndrome (AHS) and the symptom is selected from the group consisting of focal motor seizures, generalized status epilepticus, refractory convulsive status epilepticus, developmental delay, neurodevelopmental regression, renal dysfunction, hypotonia, epilepsia partialis continua, and any combination thereof.

24. The method of claim 21 or 22, wherein 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.

25. The method of claim 21 or 22, wherein 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.

26. The method of claim 21 or 22, wherein 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.

27. The method of any one of claims 1-26, wherein the subject to be treated is:(a) a pediatric patient less than 12 years old;(b) an adolescent over an age of 12 years old through an adult up to age 40; or(c) an adult over age 40.Attorney Docket No. PTZ-011WO28. The method of any one of claims 1-27, wherein the compound is l-((S)-8- chlorochroman-4-yl)-3- (2-(l-hydroxyethyl)thiazol-4-yl)urea, or a pharmaceutically acceptable salt thereof.

29. The method of any one of claims 1-28, wherein the compound penetrates the central nervous system (CNS).

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