ENPP1 inhibitors for treating or preventing hypophosphatasia

Abstract

Provided here are methods of treating or preventing hypophosphatasia (HPP) using the ENPP1 inhibitors.

Description

ENPP1 INHIBITORS FOR TREATING OR PREVENTING HYPOPHOSPHATAS1A CROSS REFERENCE TO RELATED APPLICATIONS[00011 This application claims the benefit under 35 U.S.C. §119(e) to U.S. Provisional Application Number 63 / 698,454, filed September 24, 2024, which is hereby incorporated by reference in its entirety.BACKGROUND

[0002] Hypophosphatasia (HPP) is an inherited disorder that affects the development of bones and teeth. HPP is caused by loss-of-function mutations in the ALPL gene, which provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TN SALP). This enzyme plays an essential role in mineralization, which is critical for the formation of bones that are strong and rigid and teeth that can withstand chewing and grinding. Mutations in the ALPL gene lead to the production of an abnormal version of TN SALP that cannot participate effectively in the mineralization process. A shortage of TN SALP allows several other substances, which are normally processed by the enzyme, to build up abnormally in the body. Researchers believe that a buildup of one of these compounds, inorganic pyrophosphate (PPi), underlies the defective mineralization of bones and teeth in people with HPP. ALPL gene mutations that almost completely eliminate the activity of TN SALP usually result in the more severe forms of HPP. Other mutations, which reduce but do not eliminate the activity of the enzyme, often cause the milder forms of the condition.

[0003] Hypophosphatasia (HPP) displays a wide array of symptoms that can manifest at any stage from about prenatal development through to adulthood, with the most critical conditions often observed before birth and in the early years of life. This disorder leads to the weakening and softening of bones, resulting in skeletal deformities akin to rickets, characterized by shortened limbs, unusual chest shapes, and soft skull bones in affected infants. Early infancy may also bring severe challenges, including difficulties with feeding and weight gain, respiratory issues, and elevated calcium levels in the blood (hypercalcemia), potentially causing frequent vomiting and renal complications, which can be life-threatening in some instances.

[0004] HPP presents in less severe forms during childhood or adulthood compared to its manifestation in infancy. One early indication in children is the premature loss of primary teeth, followed by potential growth issues such as short stature, bowed legs or knock knees, and enlarged wrist and ankle joints, along with an irregular skull shape. In adults, HPP primarily leads to osteomalacia, a condition where bones soften, predisposing individuals to frequent fractures, particularly in the feet and thighs, which can cause ongoing pain. Additionally, adults with HPP are prone to early loss of their adult teeth and face a higher likelihood of experiencing joint pain and inflammation.

[0005] The least severe variant of HPP, known as odontohypophosphatasia, exclusively impacts dental health. Individuals with this form of the condition often encounter issues with tooth development and experience early tooth loss. Unlike other types of HPP, odontohypophosphatasia does not lead to the skeletal deformities commonly associated with the disorder.

[0006] Novel strategies are needed to treat or prevent HPP.SUMMARY

[0007] It is contemplated that there is a safe and effective oral therapy for treating HPP. It is also contemplated that compounds of Formula I or Table 1 (e.g., Compound II), as defined herein, can be administered orally to treat HPP. It is further contemplated that compounds of Formula I or Table 1 (e.g., Compound II) can be administered once a day with reduced side effects compared to current standard of care, Asfotase alfa. Current standard of care for treating these patients is an injectable drug, Asfotase alfa, which has known side effects, such as injection site reactions, lipodystrophy, increased nephrocalcinosis, and craniosynostosis. With administration of Asfotase alfa, there can also be partial impact on the kidneys and muscles. However, when administering a compound as disclosed herein (e.g., Compound II), it is contemplated that there is still reduction of plasma PPi, musculoskeletal improvements, no injection site reactions, prevention of craniosynostosis, reduction / elimination of nephrocalcinosis, ocular calcification, muscle pain, and / or fatigue, and combinations thereof.

[0008] Provided herein are methods of treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a compound having the structure:or a pharmaceutically acceptable salt thereof, wherein:Ring C is 5- to 6-membered heteroaryl;Ring D is Ce-aryl or 5- to 6-membered heteroaryl, wherein Ring D is fused to Ring C;A is hydrogen, Ci-Cg alkyl, or Ce-aryl, each of which is optionally substituted with halogen;G is a bond, -CH2-, or -C F-CIU-:Raand Rbare independently hydrogen or Ci-Ce alkyl; or Raand Rbare taken together with the atoms to which they are attached to form a C3-Ce cycloalkyl ring; or any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring;L is a bond, linear or branched Ci-Ce alkylene, or linear or branched C2-C6 alkenylene; t is 0 or 1 ; provided that when t is 0, then L is linear or branched C2-C6 alkenylene;Z is -NRCS(O)2NH2, -NRCS(O)2CH3, -SO2NH2, -NRCC(O)CH3, -C(O)OH, -CONH2, -NRCCONH2, -CONH(OH), -B(OH)2, -P(O)(OH)2, -SO2OH, -NRCS(O)2CF3, -NRCS(O)2NHCH3, or -NRcCH2G-aryl-S(O)2NH2. each R1and R2is independently oxo, Ci-Ce alkyl, C2-C(, alkenyl, G-G, alkynyl, G-G, cycloalkyl, adamantyl, 3- to 6-membered heterocyclyl, G-aryl, 5- to 6-membered heteroaryl, -CN, halogen, G-G alkoxy, Ci-C6haloalkoxy, -OR10, -SR10, -S(O)2R10, -S(O)2NRHR12, -NR10S(O)2RH, -NRnR12, -C(O)R10, -NR10C(O)RH, -NR‘°C(O)NR11R12, -C(O)OR10, -C(O)ONRnR12, or -C(O)NR"R12, wherein each is independently optionally substituted by R9; or two R2are taken together with the atoms to which they are attached to form a C5-G, cycloalkyl, 5- to 6-membered heterocyclyl, G-aryl, or 5- to 6-membered heteroaryl, wherein each is independently optionally substituted by R9; each R9is independently selected from about the group consisting of oxo, G-G alkenyl, C2-G alkynyl, G-G cycloalkyl, 3- to 6-membered heterocyclyl, G-aryl, 5- to 6-membered heteroaryl, -CN, halogen, G-G alkoxy, G-G haloalkoxy, G-G haloalkyl, -OR13, -SR13, -S(O)2R13, -S(O)2NR14R15, - NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, - C(O)NR14R15, and G-G alkyl optionally substituted by oxo, -OH, or halogen; each Rcis independently hydrogen, G-G alkyl, G-G cycloalkyl, -(G-G alkylene)G-G cycloalkyl, 3- to 6-membered heterocyclyl, -(G-G alkylene)3- to 6-membered heterocyclyl, -(G-G alkylene)G-aryl, 5- to 6-membered heteroaryl, -(G-G alkylene)5- to 6-membered heteroaryl, G-G haloalkyl, -(G-G alkylene)OR13, -(G-G alkylene)SR13, -(G-G alkylene)S(O)2R13, -(G-G alkylene)S(O)2NR14R15, -(G-G alkylene)NR13S(O)2R14, -(G-G alkylene)NR14R15, -(G-G alkylene)C(O)R13, -(G-G alkylene)NR13C(O)R14, -(G-G alkylene)NRl3C(O)NR14R15, -(G-G alkylene)C(O)OR13, -(G-G alkylene) C(O)ONR14R15, or -(G-G alkylene)-C(O)NR14R15, wherein each is independently optionally substituted with Rd; each Rdis independently selected from about the group consisting of halogen, -OH, oxo, -CN, G- G, haloalkyl, G-G alkoxy, G-G haloalkoxy, -COOH, and G-G alkyl optionally substituted with -OH, halogen, CN, or oxo;each R10, R11, and R12is independently hydrogen, Ci-Cr, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, -(Cj-Cg alkylcnc)C;-C(, cycloalkyl, 3- to 6-membered heterocyclyl, or -(Ci-Cg alkylene)3- to 6-membered heterocyclyl, wherein each of R10, R” andR12is independently optionally substituted by oxo, C2-Cg alkenyl, C2-C6 alkynyl, -CN, halogen, Ci-Cg alkoxy, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; or R11and R12are taken together with the atom(s) to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halogen, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; each R13, R14andR15is independently hydrogen, Ci-Cg alkyl, C2-C6 alkenyl, C2-Cg alkynyl, Ci-Cg haloalkyl, Cj-Cg cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each of R10, R”, andR12is independently optionally substituted by oxo, -OH, C2-C6 alkenyl, C2-Cg alkynyl, -CN, halogen, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; or R14and R15are taken together with the atoms to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halogen, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4; provided that when Z is -NRcS(O)2CH3, -CONH2 or -C(O)OH, G is a bond, and t is 1, then L is not a bond; wherein the subject is characterized as having at least one symptom of HPP, and wherein the subject is a treatment naive subject, an enzyme replacement therapy (EZRT) intolerant / resistant subject, previously treated with EZRT, or refractory to, or has relapsed from the EZRT, and wherein the subject is: an adult with childhood-onset HPP; an adult with adult-onset HPP; a juvenile with childhood-onset HPP; or an infant with infantile HPP.

[0009] In certain embodiments, the compound is shown in Table 1, or a pharmaceutically acceptable salt thereof.

[0010] In certain embodiments, the compound is Compound 11:or a pharmaceutically acceptable salt thereof.10011] In certain embodiments, the compound is Compound III:or a pharmaceutically acceptable salt thereof.

[0012] In certain embodiments, the compound is Compound IV :or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the compound is Compound V :or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments, the compound is Compound VI:or a pharmaceutically acceptable salt thereof.10015] In certain embodiments, the compound is Compound VII:vil or a pharmaceutically acceptable salt thereof.

[0016] In certain embodiments, the compound is Compound VIII:or a pharmaceutically acceptable salt thereof.

[0017] In certain embodiments, the compound is Compound IX:or a pharmaceutically acceptable salt thereof.10018] In certain embodiments, the compound is Compound X:or a pharmaceutically acceptable salt thereof.

[0019] In certain embodiments, the compound is Compound XI:or a pharmaceutically acceptable salt thereof.[00201 In certain embodiments, the compound is Compound XII:or a pharmaceutically acceptable salt thereof.

[0021] In certain embodiments, the compound is Compound XIII:or a pharmaceutically acceptable salt thereof.

[0022] In certain embodiments, the at least one symptom of HPP comprises at least one of pathogenic or likely pathogenic ALPL gene mutation, elevated blood and / or urine levels of natural substrates, poorly healing fractures, chondrocalcinosis, nephrocalcinosis, rickets, early atraumatic loss of teeth, premature loss of deciduous teeth, short stature or linear growth failure over time, delayed motor milestones, craniosynostosis, B6 responsive seizures, incomplete bone mineralization, elevated blood and / or urine levels of inorganic pyrophosphate (PPi), elevated blood levels of phosphoethanolamine (PEA), elevated urine levels of PEA, elevated blood levels of pyridoxal 5 ’-phosphate (PLP), elevated urine levels of PLP,hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture (such as atypical femoral fractures or recurrent metatarsal fractures), HPP-related seizure, inadequate weight gain, and calcium pyrophosphate dihydrate crystal deposition.

[0023] In certain embodiments, the administering comprises a dose of about 10 mg / day-300 mg / day.

[0024] In certain embodiments, the administering comprises a dose of at least about 10 mg / day.

[0025] In certain embodiments, the administering comprises one dose per day, two doses per day, three doses per day, or one dose per two days.

[0026] In certain embodiments, administering the compounds of Formula I or Table 1 (e.g., Compound II), or a pharmaceutically acceptable salt thereof, reduces urine levels of inorganic pyrophosphate (PPi) in the subject. In certain embodiments, the urine levels of PPi is reduced by at least about 10%, 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 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0027] In certain embodiments, administering the compounds of Formula I or Table 1 (e.g., Compound II), or a pharmaceutically acceptable salt thereof, reduces plasma levels of inorganic pyrophosphate (PPi) in the subject. In certain embodiments, the plasma levels of PPi is reduced by at least about 10%, 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 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, or at least about 95%.

[0028] In certain embodiments, the method comprises improving in the subject at least one of a Radiographic Global Impression of Change (RGI-C) score, Rickets Severity Scale (RSS) score, or osteoid thickness.

[0029] In certain embodiments, the method comprises improving in the subject at least one of the functional efficacy endpoints selected from the group consisting of Peabody Developmental Motor Scales, Third Edition (PDMS-3) Score, Childhood Health Assessment Questionnaire (CHAQ) disability index score, Pediatric Outcomes Data Collection Instrument (PODCI), Percent 6-minute walk test (6MWT), Timed Up-and-Go (TUG), Lower Extremity Functional Scale (LEFS) Score, Muscle Strength Grade, 30-second Sit to Stand (STS) Test Score, handheld dynamometer (HHD), Bone mineral density Z- score using Dual-energy X-ray absorptiometry, Brief Pain Inventory - Short Form (BPI-SF) questionnaire, Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Bruininks- Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), percent predicted distance walked on a 6- minute walk test (6MWT), and modified performance-oriented mobility assessment-gait (MPOMA-G).

[0030] In certain embodiments, the method provides improved muscle strength or reduced pain.

[0031] In certain embodiments, the pain is from muscle pain and / or joint pain.

[0032] In certain embodiments, the treatment or prevention lasts at least one year, at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years or longer.BRIEF DESCRIPTION OF THE DRAWINGS

[0033] FIG. 1A-FIG. 1C illustrate reduction of plasma PPi levels in rodents and dogs after a single dose of Compound II.

[0034] FIG. 2A-FIG. 2B illustrate reduction of plasma PPi (FIG. 2A) and urine PPi (FIG. 2B) levels with various dosage in mice after a single dose of Compound II, as compared with the asfotase alfa (AA).

[0035] FIG. 3 illustrates reduction of PPi levels in Mouse urine in a dose-dependent manner after a single dose as compared to vehicle for compounds of Table 1.

[0036] FIG. 4 illustrates reduction of PPi levels in Mouse plasma in a dose-dependent manner after a single dose as compared to vehicle for compounds of Table 1.DETAILED DESCRIPTIONDefinitions

[0037] Before describing the disclosure in detail, it is to be understood that this disclosure is not limited to particular compositions or biological systems, which can, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting. As used in this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a molecule” optionally includes a combination of two or more such molecules, and the like.

[0038] The term “about” as used herein refers to the usual error range for the respective value readily known to the skilled person in this technical field. Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In case of doubt, or should there be no art recognized common understanding regarding the error range for a certain value or parameter, “about” means ± 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of this value or parameter.

[0039] It is understood that aspects and embodiments of the disclosure described herein include “comprising,” “consisting,” and “consisting essentially of aspects and embodiments.

[0040] As used herein, “at least” refers to an amount that is ^10% of the recited value and is preferably %5% of the recited value, or more preferably %2% of the recited value.

[0041] As used herein, the term “NPP” or “ENPP” refers to ectonucleotide pyrophosphatase / phosphodiesterase.

[0042] “Alkyl” refers to and includes saturated linear and branched univalent hydrocarbon structures and combination thereof, having the number of carbon atoms designated (i.e., Cj-Cio means one to tencarbons). Particular alkyl groups are those having 1 to 20 carbon atoms (a “C1-C20 alkyl”). More particular alkyl groups are those having 1 to 8 carbon atoms (a “Ci-Cs alkyl”), 3 to 8 carbon atoms (a “Cs-Cs alkyl”), 1 to 6 carbon atoms (a “Ci-Ce alkyl”), 1 to 5 carbon atoms (a “C1-C5 alkyl”), or 1 to 4 carbon atoms (a “C1-C4 alkyl”). Examples of alkyl include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, homologs and isomers of, for example, n- pentyl, n-hexyl, n-heptyl, n-octyl, and the like.

[0043] ‘'Alkenyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of olefinic unsaturation (z. e. , having at least one moiety of the formula C=C) and having the number of carbon atoms designated (z.e., C2-C10 means two to ten carbon atoms). Tire alkenyl group may be in “cis” or “trans” configurations, or alternatively in “E” or “Z” configurations. Particular alkenyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkenyl”), having 2 to 8 carbon atoms (a “C2-C8 alkenyl”), having 2 to 6 carbon atoms (a “C2-C6 alkenyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkenyl”). Examples of alkenyl include, but are not limited to, groups such as ethenyl (or vinyl), prop-l-enyl, prop-2 -enyl (or allyl), 2-methylprop-l-enyl, but-l-enyl, but-2-enyl, but-3-enyl, buta- 1,3 -dienyl, 2-methylbuta- 1,3 -dienyl, homologs and isomers thereof, and the like.

[0044] “Alkylene” as used herein refers to the same residues as alkyl, but having bivalency. Particular alkylene groups are those having 1 to 6 carbon atoms (a “Ci-Ce alkylene”), 1 to 5 carbon atoms (a “C1-C5 alkylene”), 1 to 4 carbon atoms (a “C1-C4 alkylene”) or 1 to 3 carbon atoms (a “C1-C3 alkylene”).Examples of alkylene include, but are not limited to, groups such as methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-), butylene (-CH2CH2CH2CH2-), and the like. “Alkenylene” as used herein refers to the same residues as alkenyl, but having bivalency.

[0045] “Alkynyl” as used herein refers to an unsaturated linear or branched univalent hydrocarbon chain or combination thereof, having at least one site of acetylenic unsaturation ( / .<?., having at least one moiety of the formula C=C) and having the number of carbon atoms designated (z.e., C2-C10 means two to ten carbon atoms). Particular alkynyl groups are those having 2 to 20 carbon atoms (a “C2-C20 alkynyl”), having 2 to 8 carbon atoms (a “C2-C8 alkynyl"). having 2 to 6 carbon atoms (a “C2-C6 alkynyl”), or having 2 to 4 carbon atoms (a “C2-C4 alkynyl”). Examples of alkynyl include, but are not limited to, groups such as ethynyl (or acetylenyl), prop-l-ynyl, prop-2 -ynyl (or propargyl), but-l-ynyl, but-2-ynyl, but-3-ynyl, homologs and isomers thereof, and the like.

[0046] “Aryl” refers to and includes polyunsaturated aromatic hydrocarbon groups. Aryl may contain additional fused rings (e.g., from about 1 to 3 rings), including additionally fused aryl, hctcroar l. cycloalkyl, and / or heterocyclyl rings. In one variation, the ar l group contains from about 6 to 14 annular carbon atoms. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, biphenyl, and the like.

[0047] ‘'Carbonyl” refers to the group C=O.

[0048] “Cycloalkyl” refers to and includes cyclic univalent hydrocarbon structures, which may be fully saturated, mono- or polyunsaturated, but which are non-aromatic, having the number of carbon atoms designated (e.g., C1-C10 means one to ten carbons). Cycloalkyl can consist of one ring, such as cyclohexyl, or multiple rings, such as adamantly, but excludes aryl groups. In certain embodiments, cycloalkyl comprising more than one ring may be fused, spiro or bridged, or combinations thereof. In certain embodiments, cycloalkyl is a cyclic hydrocarbon having from about 3 to 13 annular carbon atoms. In certain embodiments, cycloalkyl is a cyclic hydrocarbon having from about 3 to 8 annular carbon atoms (a “Cj-Cs cycloalkyl”). Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 1 -cyclohexenyl, 3 -cyclohexenyl, cycloheptyl, norbomyl, and tire like.

[0049] “Halo” or “halogen” refers to elements of the Group 17 series having atomic number 9 to 85. In certain embodiments, halo groups include fluoro, chloro, bromo, and iodo. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc. refer to aryl and alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be but are not necessarily tire same halo: thus 4- chloro-3 -fluorophenyl is within the scope of dihaloaryl. An alkyl group in which each hydrogen is replaced with a halo group is referred to as a “perhaloalkyl.” In certain embodiments, a perhaloalkyl group is trifluoroalkyl (-CF3). Similarly, “perhaloalkoxy” refers to an alkoxy group in which a halogen takes the place of each H in the hydrocarbon making up the alkyl moiety of the alkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy (-OCF3).

[0050] "Hctcroaryl" refers to and includes unsaturated aromatic cyclic groups having from about 1 to 10 annular carbon atoms and at least one annular heteroatom, including but not limited to heteroatoms such as nitrogen, oxygen and sulfur, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heteroaryl group can be attached to the remainder of the molecule at an annular carbon or at an annular heteroatom. Hctcroaryl may contain additional fused rings (e.g., from about 1 to 3 rings), including additionally fused aryl, heteroaryl, cycloalkyl, and / or heterocyclyl rings. Examples of heteroaryl groups include, but are not limited to imidazolyl, pyrrolyl, pyrazolyl, 1.2.4-triazolyl, thiophenyl, furanyl, thiazolyl, isothiazolyl, 1,3,4-thiadiazolyl oxazolyl, isoxazolyl, 1,3,4-oxadiazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, indolyl, indazolyl. benzoimidazolyl, pyrrolopyridinyl, pyrrolopyridazinyl, pyrrolopyrimidinyl, pyrazolopyridinyl, pyrazolopyrimidinyl, imidazopyridinyl, purinyl, benzofiiranyl, furopyridinyl, benzooxazolyl, benzothiophenyl, benzothiazolyl, oxazolopyridinyl, thiazolopyridinyl, thienopyridinyl, quinolinyl,quinolonyl, naphthyridinyl, quinazolinyl, pyridopyrimidinyL cinnolinyl, or pyridopyridazinyl, and the like.

[0051] “Heterocycle” or “heterocyclyl” refers to a saturated or an unsaturated non-aromatic group having from about 1 to 10 annular carbon atoms and from about 1 to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and the like, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quatemized. A heterocyclyl group may have a single ring or multiple condensed rings, but excludes heteroaryl groups. A heterocycle comprising more than one ring may be fused, spiro or bridged, or any combination thereof. In fused ring systems, one or more of the fused rings can be aryl or heteroaryl. Examples of heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, oxetanyl, morpholinyl, thiomorpholinyl, azepanyl tetrahydropyranyl, dihydropyranyl, piperidinyl, piperazinyl, pyrrolidinyl, thiazolinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, and the like.

[0052] “Oxo” refers to the moiety =0.

[0053] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted or substituted by one or more (e.g., 1, 2, 3, 4, or 5) of the substituents listed forthat group in which the substituents may be the same of different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. In some embodiments, an optionally substituted group has 1 to 2, 2 to 5, 3 to 5, 2 to 3, 2 to 4, 3 to 4, 1 to 3, 1 to 4, or 1 to 5 substituents.

[0054] As used herein, the term “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively non-toxic, i.e.. the material may be administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0055] “Pharmaceutically acceptable salt” is meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein. When compounds as disclosed herein contain relatively acidic functionalities, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent. Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt. When compounds as disclosed herein contain relatively basic functionalities, acid addition salts can be obtained by contacting tire neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derived from about inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, phosphoric, partially neutralized phosphoric acids, sulfuric, partially neutralized sulfuric, hydroiodic, or phosphorous acids and the like, as well as the salts derived from about relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like. Certain specific compounds of the present disclosure may contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., Mack Publishing Company, Easton, Pa.. (1985) and Journal of Pharmacal Science. 66:2 (1977), each of which is incorporated herein by reference in its entirety.

[0056] As used herein, the terms "treat” or "treatment” refer to therapeutic treatment, wherein the object is to slow down (lessen) an undesired physiological change or disorder, such as the progression of a condition or disorder. Beneficial or desired clinical results include, but are not limited to, alleviation of symptoms, diminishment of extent of disease, stabilized (i.e., not worsening) state of disease, delay or slowing of disease progression, amelioration or palliation of the disease state, and remission (whether partial or total), whether detectable or undetectable. "Treatment” can also mean prolonging survival as compared to expected survival if not receiving treatment. Those in need of treatment include those already with the condition or disorder as well as those prone to have the condition or disorder.

[0057] The term “prevent” or “prevention” means any treatment of a disease or condition that causes the clinical symptoms of the disorder or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or condition.

[0058] A “disorder” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal’s health continues to deteriorate.

[0059] The terms “effective amount,” “pharmaceutically effective amount,” and “therapeutically effective amount” refer to an amount that may be effective to elicit the desired biological or medical response, including the amount of a compound or a polypeptide that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The effective amount will vary depending on the compound or the polypeptide, the disease and its severity and the age. weight, etc., of the subject to be treated. The effective amount can include a range of amounts. A pharmaceutically effective amount includes amounts of an agent which are effective when combined with other agents.

[0060] By “subject” or “individual” or “animal” or “patient” or “mammal,” is meant any subject, particularly a mammalian subject, for whom diagnosis, prognosis, or therapy is desired. Mammaliansubjects include humans, domestic animals, farm animals, and zoo, sport, or pet animals such as dogs, cats, guinea pigs, rabbits, rats, mice, horses, cattle, cows, and so on.

[0061] As used herein, phrases such as “to a patient in need of treatment” or “a subject in need of treatment” includes subjects, such as mammalian subjects, that would benefit from about administration of an antibody or composition of the present disclosure used, e.g. , for detection, for a diagnostic procedure and / or for treatment.

[0062] As used herein the terms “alteration,” “defect,” “variation,” or “mutation” refer to a mutation in a gene in a cell that affects the function, activity, expression (transcription or translation) or conformation of the polypeptide it encodes. Mutations encompassed by the present disclosure can be any mutation of a gene in a cell that results in the enhancement or disruption of the function, activity’, expression or confonnation of the encoded polypeptide, including the complete absence of expression of the encoded protein and can include, for example, mis sense and nonsense mutations, insertions, deletions, frameshifts and premature terminations. Without being so limited, mutations encompassed by the present disclosure may alter splicing the mRNA (splice site mutation) or cause a shift in the reading frame (frameshift).

[0063] By “pain” as used herein refers to physical suffering or discomfort caused by HPP, such as bone pain. For instance, symptoms of pain can include, e.g., soreness, tightness, or stiffness. The severity of pain can vary between patients (e.g., chronic pain or acute pain). In particular, chronic pain refers to pain that lasts longer than three to six months or pain that extend beyond the expected period of healing. In contrast, acute pain refers to pain that typically lasts less than three to six months. As described herein, therapeutic compositions (e.g., including the compounds provided herein) can be administered to a patient suffering from about pain (e.g., bone pain) in an amount sufficient to relieve or at least partially relieve the symptoms of pain (e.g, discomfort, soreness, tightness, or stiffness) and its complications (e.g., fatigue, sleeplessness, weakened immune system, depression, anxiety, stress, irritability, or disability). In certain embodiments of the present disclosure, the pain can be muscle pain and / or joint pain.

[0064] “Quality of Life (QoL) questionnaires” are standardized tools used to measure an individual's overall well-being and satisfaction with life, covering various aspects such as physical health, psychological state, level of independence, social relationships, personal beliefs, and their relationship to salient features of their environment. These questionnaires are used in a wide range of fields, including healthcare, psychology, and social science research. They can be generic, suitable for use across different diseases, populations, and interventions, or disease-specific, designed to assess the impact of a specific condition on an individual's quality of life. QoL questionnaires typically consist of a series of questions or statements where responses are quantified and then summed to produce a score that represents an individual's quality of life. The design of these instruments is based on a conceptual framework that defines what quality of life means for the target population, ensuring that the questionnaire measures whatit intends to accurately and reliably. These tools are particularly important in clinical trials and health outcomes research to assess the effectiveness of medical treatments not just in terms of clinical or physiological outcomes, but also in how they affect a patient's daily life and overall satisfaction. They can also guide clinical decision-making, helping healthcare providers understand the patient's perspective and what matters most to them in tenns of health and treatment outcomes.

[0065] In certain embodiments of the present disclosure, the level of pain is evaluated by Brief Pain Inventory - Short Form (BPI-SF) questionnaire. The BPI-SF questionnaire is a widely used self-reporting tool designed to assess the severity of pain and the impact of pain on daily functions. It is a shorter version of the original Brief Pain Inventory and focuses on key areas to efficiently evaluate a patient's pain experience. The BPI-SF asks patients to rate their pain at its worst, least, average, and current levels on a scale from about 0 (no pain) to 10 (pain as bad as you can imagine). Additionally, it assesses how pain interferes with general activity, mood, walking ability, normal work (both outside the home and housework), relationships with others, sleep, and enjoyment of life, using a similar 0 to 10 scale. This tool is useful in both clinical settings for pain management and research studies to quantify the impact of pain on an individual’s life, allowing healthcare providers to tailor treatments to the patient's specific needs and measure the effectiveness of pain management strategies over time.

[0066] The terms “Pediatric Outcomes Data Collection Instrument” or “PODCI,” as used herein, refer to a questionnaire used to assess overall health, incidence of pain, and ability to perfonn ADLs of patients under 19 years of age, particularly in patients with chronic health disorders, such as patients with HPP. For a description of the PODCI, see Plint et al. (J. Pediatr. Orthop. 23(6): 788-790, 2003), hereby incorporated by reference in its entirety. The questionnaire may be completed by the patient or by a parent / guardian of the patient with knowledge of tire patient's condition. Hie eight scales generated from about the PODCI include the following: 1) the upper extremity and physical function scale to measure difficulty encountered in performing daily personal care and student activities; 2) the transfer and basic mobility scale to measure difficulty experienced in performing routine motion and motor activities in daily activities; 3) the sports / physical functioning scale to measure difficulty or limitations encountered in participating in more active activities or sports; 4) the pain / comfort scale to measure the level of pain experienced during the past week; 5) the treatment expectations scale to measure the long temi expectations of treatment; 6) the happiness scale to measure overall satisfaction with personal looks and sense of similarity to friends and others of own age; 7) the satisfaction with symptoms scale to measure the patients acceptance of current limitations should this be a life-long state; and 8) the global functioning scale, which is a general combined scale calculated from about the first four scales listed above.Standardized scores are generated from about a series of questions in the PODCI and converted to a 0 to 100 scale, in which 0 represents significant disability and 100 represents less disability.

[0067] The '‘Peabody Developmental Motor Scales, Third Edition (PDMS-3)” as used herein, is an early childhood motor development program comprised of one supplemental and five core subtests providing in-depth assessment, training, and remediation of gross and fine motor skills in individuals ages 0 to 5 years, 11 months. Tire five core subtests include the following: 1) Body Control. This subtest measures the ability to move tire limbs and trunk, postural reactions, standing, bending, extending, stooping, balancing, jumping upward. It is an estimate of the child's ability to sustain control of his or her body within its center of gravity and retain equilibrium; 2) Body Transport. This subtest measures the ability to make movements that propel the child from about one location to another, such as rolling, crawling, creeping, walking, running jumping forward and sideward, sliding, hopping, and skipping; 3) Object Control. This subtest measures the ability to coordinate motor movements that require the incorporation of perception and movement, such as throwing, catching, bouncing, and kicking a ball; 4) Hand Manipulation. This subtest measures the ability to move the hands and fingers (and anns as appropriate) to complete tasks and measure dexterity. This includes manipulation of objects such as blocks, cups, and drawing instruments; and 5) Eye-Hand Coordination. This subtest measures the ability to interpret visual stimuli in coordination with hand-finger movements. It is an estimate of the child's ability to integrate and use his or her visual perceptual skills to perfonn complex eye-hand coordination tasks. The supplemental subtest is physical fitness, which measures the ability to perform activities like push-ups, sit ups, repetitive jumps, running speed, throwing for distance, and sit and reach / flexibility.

[0068] As used herein, '‘Six Minute Walk Test” andC'6MWT” refer to a standardized test to assess walking ability of a patient (e.g., a child having HPP), in particular, the ability of the patient to lift and set down each foot in turn. See the American Thoracic Society statement: guidelines for the six-minute walk test (American Journal of Respiratory and Critical Care Medicine. 166(1): 111-7, 2002), hereby incorporated by reference in its entirety. Tire 6MWT is determined from about tire distance (e g., in meters) that a patient walks on a flat, hard surface in a period of six minutes. The 6MWT distance can then be compared to the 6MWT distance of the patient at baseline, the 6MWT distance of an untreated subject (e.g., an untreated subject of about the same age, height, and / or gender), or the 6MWT distance of a healthy subject (e.g., a healthy subject of about the same age, height, and / or gender) and expressed as a percentage to determine the 6MWT value.

[0069] The term “RGI-C Responder” refers to a classification based on the Radiographic Global Impression of Change (RGI-C) scale, a tool used to evaluate changes in bone structure and disease progression or improvement in patients with HPP. The RGI-C scale is designed to provide a systematic assessment of radiographic images, such as X-rays, to judge the efficacy of treatments for skeletal disorders. An "RGI-C Responder" in HPP patients is someone who shows a clinically meaningful improvement in bone radiographs over a specified period, indicating a positive response to treatment.This improvement can include enhanced bone mineralization, correction of skeletal abnormalities, or other radiographic signs of bone health progress. The RGI-C scale helps clinicians quantify the benefits of treatments like enzyme replacement therapy, making it possible to monitor the effectiveness of therapeutic interventions and adjust treatment plans to optimize patient outcomes in HPP management. The RGI-C scale typically involves a scoring system where changes in radiographic images are rated on a scale (a 7-point scale in which a rating of -3 represents severe worsening and a rating of +3 indicates near or complete healing): "Significantly Worse (-3)," "Moderately Worse (-2)," "Slightly Worse (-1)," "Unchanged (0)," "Slightly Improved (+1)," "Moderately Improved(+2)," "Significantly Improved(+3)".

[0070] Tire terms “Bruininks-Oseretsky Test of Motor Proficiency 2nd Edition” or “BOT-2,” as used herein, refer to the second edition of a standardized test of gross and fine motor performance for patients, e.g., including adolescent and adult patients having HPP. See Bruininks, R. H. (2005). Bruininks- Oseretsky Test of Motor Proficiency, (BOT-2). Minneapolis, Minn. Pearson Assessment, hereby incorporated by reference in its entirety. The BOT-2 is administered individually to assess gross and fine motor skills of a range of patients. The BOT-2, for example, can be used to evaluate physical impairments and mobility restrictions in patients having HPP (e.g., adults and adolescents having HPP). The BOT-2 provides composite BOT-2 scores in the following exemplary areas: strength, running speed and agility, fine motor precision, fine motor integration, manual dexterity, bilateral coordination, balance, and upperlimb coordination. For example, a BOT-2 strength total score can be determined by having a patient perform sit-ups, v-ups, standing long jump, wall sit, and push-ups. A running speed and agility total score can be determined by having a patient step over a balance beam or perform a shuttle run, two-legged side hop, or one-legged side hop. Both BOT-2 total strength and BOT-2 running speed and agility total scores range from about 0 to 25, in which a score of about 10 to 25 is considered representative of healthy subjects. Normative scores for the strength and running speed and agility are 15+ / - 5. Adult and adolescent scores are not normed (does not use the scaled score), and thus higher point values represent better performance. Either average or median scores may be used, with median scores preferred for smaller sample sizes or smaller data sets.

[0071] Tire terms “modified Performance Oriented Mobility Assessment-Gait” and “mPOMA-G,” as used herein, refer to a modified version of the Performance Oriented Mobility Assessment — Gait (POMA-G), such as a POMA-G that is modified to provide improved sensitivity’ for gait impainnents in POMA-G components that pertain to HPP patients (e.g.. a child or an adolescent with HPP). The POMA is a validated tool that consists of 2 subtests: tire POMA-G (Gait) and the POMA-B (Balance). See Tinetti et al. (Am J Med 80:429-434, 1986) for a description of the POMA-G; hereby incorporated by reference in its entirety. Gait performance of an HPP patient (e.g., a child or an adolescent with HPP) can be assessed using an mPOMA-G test, e.g., in which the POMA-G analysis has been modified to remove theless appropriate components, i.e., the initiation of gait and path components, of the POMA-G. For example, the mPOMA-G analysis can provide a total score of 12 points, similarly to the POMA-G components, of step length and height, step symmetry, step continuity, trunk sway, and walking stance, in which a score of 12 indicates no gait impairments, and lower scores indicate gait impairments.

[0072] The terms "Childhood Health Assessment Questionnaire" or "CHAQ." as used herein refer to a questionnaire that is used to assess the health status (e.g., ability to perform activities of daily living (ADLs) and incidence of pain) of patients of 1 to 19 years of age, such as patients with HPP. For a description of the CHAQ index, see Bruce & Fries (J. Rheumatol. 30(1 ): 167-178.. 2003), hereby incorporated by reference in its entirety. The CHAQ may be administered by interview or self-report for children greater than 8 years of age. The CHAQ includes eight sub-scales for dressing / grooming, arising, eating, walking, hygiene, reach, grip, and activities. Hie range of scores within each category is from about 0 to 3. in which a score of 0 indicates without any difficulty; a score of 1 indicates with some difficulty; a score of 2 indicates with much difficulty; and a score of 3 indicates that the patient is unable to perform the activity. The CHAQ index may also be used to determine the presence and severity of pain.

[0073] The “Timed Up-and-Go” or “TUG” test, as used herein, retains its fundamental purpose of assessing mobility, balance, and walking ability. The interpretation of TUG test results in HPP patients, like in other populations, considers the time taken to complete the test, with longer times indicating potential mobility issues or a higher risk of falls. The total TUG duration (TTD) is usually the only outcome measure, with TTD shortening indicating the patient's improvement. Mobility is assessed based on time to complete the test: < 10 seconds = normal; < 20 seconds = good mobility; can walk outside alone; does not require a walking aid; < 30 seconds = walking and balance problems; cannot walk outside alone; requires walking aid. A cut-off of 13.5 seconds or longer is reported to be predictive of falling risk.

[0074] The “Lower Extremity Functional Scale” or “LEFS” is a questionnaire used to assess the functional status of individuals with disorders of the lower extremities. It is particularly valuable in gauging a patient’s difficulty in performing everyday tasks due to lower limb issues. The LEFS consists of 20 questions, each asking the respondent to rate their level of difficulty in perfonning different activities that involve the lower extremities, such as walking, going up or down stairs, and carrying objects. Responses are scored on a scale, with higher scores indicating better functional performance. In the context of Hypophosphatasia (HPP). the LEFS can serve several important roles: 1) Baseline Functional Assessment: The LEFS can help establish a baseline of functional abilities in individuals diagnosed with HPP. This is crucial for understanding the impact of the disease on lower limb function and for planning treatment and rehabilitation strategies; 2) Monitoring Disease Progression: Regular administration of the LEFS over time can provide valuable information on the progression of HPP and itsimpact on lower extremity function. This can help in adjusting treatment plans as needed; 3) Evaluating Treatment Efficacy: For HPP patients undergoing various treatments, including enzyme replacement therapy, physical therapy, or surgical interventions, the LEFS score can be a useful outcome measure to evaluate the effectiveness of these interventions in improving lower limb function; and 4) Guiding Rehabilitation Programs: The detailed information provided by the LEFS on specific areas of difficulty can help healthcare providers tailor rehabilitation programs to the unique needs of HPP patients, focusing on improving those activities that are most challenging for them. The LEFS is appreciated for its simplicity, reliability, and sensitivity to changes in lower extremity function over time. However, when using the LEFS with HPP patients, it is important to consider the specific manifestations of the disease that may affect lower limb function, such as bone fragility, muscle weakness, and pain. Tire interpretation of LEFS scores should be integrated into a comprehensive clinical assessment, taking into account other aspects of the patient’s health and overall functional abilities. The total LEFS score ranges from about 0 to 80 with higher scores indicating better lower extremity function. And the total LEFS score can be interpreted as 0-20: Severe dysfunction, 21-40: Moderate dysfunction, 41-60: Mild dysfunction and 61- 80: Minimal or no dysfunction.

[0075] The 30-second Sit to Stand (STS) Test is a functional exercise test used to assess lower body strength, endurance, and balance, ft measures how many times an individual can stand up from about a seated position and then sit back down in a chair within a 30-second time frame without using their arms for support. For individuals with HPP, this test can provide valuable information regarding their lower extremity strength and functional mobility. It helps in identifying the degree to which HPP has impacted their physical capabilities, especially those related to movements that are essential for daily activities. The test is also useful for monitoring changes in physical function over time, assessing the effectiveness of treatments or physical therapy interventions aimed at improving muscle strength and endurance, and guiding the development of personalized rehabilitation programs. By evaluating the number of repetitions completed, healthcare providers can gauge the severity of functional limitations, track progress, and adjust treatment plans accordingly to enhance the quality of life for patients with HPP.

[0076] Tire measurement of “handheld dynamometer” is a specific clinical assessment aimed at quantifying the muscle strength of the grip strength, knee flexion, knee extension, hip flexion, hip extension, or hip abduction. Tire hip extensors and abductors play critical roles in walking, standing, and maintaining balance. This non-invasive. practical method allows for the direct measurement of muscle strength, offering objective data crucial for diagnosing HPP, tracking disease progression, and tailoring rehabilitation and treatment plans. By quantifying muscle strength, healthcare providers can better understand the extent of muscle involvement, monitor changes over time, and evaluate the effectiveness of various interventions like enzyme replacement therapy, physical therapy, or surgery. The grip andmuscle strength of subjects having or being prone to HPP can be assessed using Hand Held Dynamometry (HHD). For example, knee flexion and extension and also hip flexion, extension, and abduction of a subject having or being prone to a muscle weakness disease can be measured using, e.g., a MICR0FET2™ Dynamometer, while grip strength of the subject can be measured using, e.g., a Jamar Grip Dynamometer. In particular, the administrator holds the dynamometer stationary, and the subject exerts a maximal force against the dynamometer. Peak force data is collected in pounds, then converted to Newtons (N). Torque values are then calculated using limb length in N-meters. The torque value can then be compared to the torque value of, e.g., a normal subject of about the same age, the same gender, and / or the same height, and expressed as a percentage value to generate the HHD value of the subject.

[0077] The Bone Mineral Density (BMD) Z-score, obtained through Dual-energy X-ray Absorptiometry (DXA), is a critical parameter. DXA is a leading diagnostic tool used to measure bone density and assess the risk of fractures. The Z-score is a statistical measurement that compares an individual's bone density to the expected bone density for a person of the same age, sex, and size. A Z-score is expressed in standard deviation units from about the mean (average) value for the population. In the context of HPP, a lower Z-score indicates a lower bone density compared to what is typically expected, highlighting the severity of bone involvement in the patient. Regular DXA assessments allow for monitoring disease progression and assessing the effectiveness of treatments aimed at improving bone health, such as supplementation, physical therapy, or enzyme replacement therapy. Particularly crucial for children and adolescents due to their developing bones, and significant for adults to reduce fracture risks, the BMD Z- score serves as a fundamental metric in tailoring treatment strategies, guiding clinical decisions, and improving patient outcomes in individuals with HPP. BMD Z-score ranges as follows: 1) +2.0 or higher: A Z-score in this range signifies that an individual's bone density is significantly above the average for their age, sex, and body size. While uncommon, such elevated scores may occasionally highlight health conditions or factors contributing to increased bone density; 2) Between -2.0 and +2.0: This range is considered normal, suggesting the individual's bone density aligns with the average expected for people of the same age, sex, and body size category; and 3) -2.0 or lower: Signifies bone density substantially below what is expected for the individual's age, sex, and size, indicating a potential concern for bone health that may require further exploration, though not diagnosing any specific condition on its own.

[0078] The terms “Bayley Scales of Infant and Toddler Development, 3rd Edition” or “BSID-III” as used herein refer to a standardized series of measurements used to assess the motor (fine and gross), language (receptive and expressive), and cognitive development of patients, e.g., infants and toddlers. See Bayley, (2006). Bayley scales of infant and toddler development: administration manual. San Antonio, Tex.: Harcourt Assessment, hereby incorporated by reference in its entirety. In particular, the BSID-III is designed to assess infants and young children. The BSID-III measurements include a series ofdevelopmental play tasks to be administered to the patient. Raw scores of successfully completed items are converted to scaled scores. The scaled scores are then used to determine the patient's performance compared to healthy, age-adjusted patients. The BSID-III can also include the Social-Emotional Adaptive Behavior Questionnaire, which is completed by the parent / guardian, to establish the range of adaptive behaviors of the patient. For example, measurements for determining the BSID-III score (e.g., the BSID- III gross motor function score) can include prehension, perceptual-motor integration, motor planning and speed, visual tracking, reaching, object grasping, object manipulation, functional hand skills, responses to tactile information, movement of the limbs and torso, static positioning, dynamic movement, balance, and motor planning. These patient measurements are then converted into a BSID-III scaled score (e.g., the BSID-III gross motor function scaled score) ranging from about 0 to 14, in which scores of about 7 to about 13 are considered the normal range of healthy patients.

[0079] Enzyme Replacement Therapy (EZRT) for HPP is a targeted treatment approach designed to address the underlying cause of this rare, inherited metabolic disorder. EZRT for HPP involves the administration of a recombinant form of TNSALP, such as asfotase alfa (STRENSIQ®), which is specifically designed to replace the missing or malfunctioning enzyme in patients with HPP, thereby helping to restore normal ALP activity levels. This therapy aims to improve bone mineralization, reduce skeletal abnormalities, enhance physical mobility, and improve overall quality of life for individuals with HPP. Asfotase alfa is typically administered via subcutaneous injection and is the first treatment specifically approved for the management of pediatric-onset HPP, though its benefits extend to affected individuals of all ages depending on the severity and presentation of the disease. By "asfotase alfa" is meant a human TNSALP (hTNSALP) fusion protein formulated for the treatment of HPP. Asfotase alfa is a fusion protein including a soluble glycoprotein of two identical polypeptide chains. The structure of each polypeptide chain includes the catalytic domain of hTNSALP, the human immunoglobulin Fc domain, and a deca-aspartate peptide used as a bone targeting domain (the structure hTNSALP-Fc-Dio). The two polypeptide chains are covalently linked by two disulfide bonds. Asfotase alfa has been approved under the trade name STRENSIQ® (Alexion Pharmaceuticals, Inc.) in the United States in 2015.

[0080] The “Rickets Severity Scale (RSS) score” is a diagnostic tool used to assess the severity of rickets, a bone condition that leads to softening and weakening of the bones, primarily in children. This condition is commonly associated with vitamin D deficiency but can also occur in various metabolic disorders, including Hypophosphatasia (HPP). The RSS score quantifies the severity of rickets based on radiographic findings, providing a standardized method to evaluate the skeletal abnormalities associated with the condition. It typically involves the examination of X-rays from about the knees and wrists of the affected individual, two areas commonly impacted by rickets. The RSS is calculated by assessing features such as growth plate widening, metaphyseal cupping and fraying, metaphyseal splaying. Each of thesefeatures is graded, and the scores are combined to provide an overall severity score. The score can range from about 0 (indicating no evidence of rickets) to a higher value that indicates more severe rachitic changes. The exact scoring system can vary, but it often involves a scale from about 0 to 10 or more, with specific criteria defined for each score level. For example, 0 represents no signs of rickets; 1-3 represents mild rickets, with slight widening of the growth plates and minimal metaphyseal abnormalities; 4-6 represents moderate rickets, with clear evidence of growth plate widening, moderate metaphyseal cupping and fraying, and some metaphyseal splaying; and 7-10 represents severe rickets, with significant growth plate widening, severe metaphyseal abnormalities including marked cupping, fraying, and splaying. Given the variability in scoring systems and the need for precise radiographic evaluation, healthcare professionals typically interpret RSS scores within the broader context of a patient's clinical presentation, biochemical markers, and other diagnostic findings.[00811 ‘ ‘Osteoid thickness” refers to the measurement of the non-mineralized, newly formed bone matrix layer, known as osteoid, which is a critical component in the bone formation process. Enzyme alkaline phosphatase (ALP) plays a vital role in bone mineralization by hydrolyzing inorganic pyrophosphate (PPi), a potent inhibitor of mineralization. In HPP, the lack of ALP activity leads to an accumulation of PPi, which inhibits calcium and phosphate from about being deposited into the bone matrix, resulting in the persistence of osteoid tissue that cannot properly mature into hard, mineralized bone. Increased osteoid thickness can indicate a significant mineralization defect. The osteoid layer in healthy individuals is typically thin, reflecting a balanced and efficient process of bone formation and mineralization. However, in conditions like HPP, the osteoid layer can be markedly thicker due to the impaired mineralization process. This increased thickness can be observed and quantified through bone histomorphometry, a microscopic examination of bone tissue. The measurement of osteoid thickness, along with other histomorphometric parameters such as osteoid volume and osteoid surface, helps in assessing the severity of the mineralization defect in patients with HPP. It provides valuable insights into the effectiveness of treatments aimed at improving bone mineralization and overall bone health in these patients. For instance, enzyme replacement therapy in HPP aims to reduce the accumulation of PPi by substituting the deficient ALP, thereby potentially normalizing osteoid thickness over time by improving the bone's ability to mineralize properly. In healthy individuals, the normal range of osteoid thickness is typically between 3 to 12 micrometers (pm). This range indicates a balanced bone remodeling process, where new bone formation and mineralization are proceeding efficiently. In HPP, due to the deficiency of ALP activity, there is an accumulation of PPi, a potent inhibitor of mineralization. This leads to an increase in osteoid thickness. While specific values can vary among individuals, osteoid thickness in HPP patients can be significantly higher than the upper limit of the normal range, often exceeding 12 pm. Theexact thickness can vary widely depending on the severity of the disease, the age of the patient, and other individual factors.

[0082] “Muscle Strength Grade”, often assessed using the Medical Research Council (MRC) Muscle Scale, is a standardized method for evaluating and documenting muscle strength in patients. This grading system is particularly relevant in various medical conditions that can affect muscle strength. In HPP, muscle weakness can be a significant clinical feature, affecting patients' mobility and quality of life. The MRC Scale is a widely used clinical tool to assess muscle strength on a scale of 0 to 5, with the following grades: 0: No muscle contraction detected (paralysis); 1 : Trace of muscle contraction, but no significant movement at the joint; 2: Active movement possible with gravity eliminated; 3: Active movement against gravity but not against resistance; 4: Active movement against gravity and some resistance but weaker than normal; 5: Normal muscle strength.ENPP1 inhibitors

[0083] Ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPPl) is an ectoenzyme which hydrolyzes ATP into PPi and AMP in the extracellular space. PPi functions as a potent inhibitor of hydroxyapatite (HAP) crystal growth, which is the inorganic mineral component of calcium phosphate and critical for bone mineralization. As ENPP1 is the primary source of PPi, inhibition of this enzyme represents a promising therapeutic approach for the treatment of HPP. Normalizing extracellular PPi levels by targeting ENPP1 could provide significant relief from about the severe symptoms of this debilitating disease. Targeted therapeutics that inhibit ENPP1 activity or neutralize PPi could lead to effective interventions for HPP.

[0084] The present disclosure provides a compound which inhibits hydrolysis of ATP via ENPP1 inhibition. In some embodiments, the compound is a compound described in US20220135598A1, which is incorporated by reference herein. In some embodiments, the compound has the below structure:or a pharmaceutically acceptable salt thereof, wherein:Ring C is 5- to 6-membered heteroaryl;Ring D is Cg-aryl or 5- to 6-membered heteroaryl, wherein Ring D is fused to Ring C;A is hydrogen, Ci-Cg alkyl, or Cg-aryl, each of which is optionally substituted with halogen;G is a bond, -CH2-, or -CH2-CH2-;Raand Rbare independently hydrogen or Ci-Cg alkyl; or Raand Rbare taken together with the atoms to which they are attached to form a C3-Cg cycloalkyl ring; or any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring;L is a bond, linear or branched Ci-Cg alkylene, or linear or branched C2-Cg alkenylene; t is 0 or 1 ; provided that when t is 0, then L is linear or branched C2-Cg alkenylene;Z is -NRCS(O)2NH2, -NRCS(O)2CH3, -SO2NH2, -NRCC(O)CH3, -C(O)OH, -CONH2, -NRCCONH2, -CONH(OH), -B(OH)2, -P(O)(OH)2, -SO2OH, -NRcS(O)2CF3, -NRCS(O)2NHCH3, or -NRcCH2C6-aryl-S(O)2NH2. each R1and R2is independently oxo, Ci-Cg alkyl, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, adamantyl, 3- to 6-membered heterocyclyl, Cg-aryl, 5- to 6-membered heteroaryl, -CN, halogen, Ci-C6alkoxy, Ci-C6haloalkoxy, -OR10, -SR10, -S(O)2R10, -S(O)2NRnR12, -NRl0S(O)2RH, -NR”R12, -C(O)R10, -NR10C(O)RH, -NRl0C(O)NRI 1R12, -C(O)OR'°, -C(O)ONRnR12, or -C(O)NRnR12, wherein each is independently optionally substituted by R9; or two R2are taken together with the atoms to which they are attached to form a Cs-Cg cycloalkyl, 5- to 6-membered heterocyclyl, Cg-aryl, or 5- to 6-membered heteroaryl, wherein each is independently optionally substituted by R9; each R9is independently selected from about the group consisting of oxo, C2-Cg alkenyl, C2-Cg alkynyl, C3-Cg cycloalkyl, 3- to 6-membered heterocyclyl, Cg-aryl, 5- to 6-membered heteroaryl, -CN, halogen, Ci-C6alkoxy, Ci-C6haloalkoxy, Cj-Cg haloalkyl, -OR13, -SR13, -S(O)2R13, -S(O)2NR14R15, - NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, - C(O)NR14R15, and Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; each Rcis independently hydrogen, Ci-Cg alkyl, C3-Cg cycloalkyl, -(Ci-Cg alkylene)C3-Cg cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-Cg alkylene)3- to 6-membered heterocyclyl, -(Ci-Cg alkylcncjCg-aryl, 5- to 6-membered heteroaryl, -(Ci-Cg alkylene)5- to 6-membered heteroaryl, Cj-Cg haloalkyl, -(Ci-Cg alkylene)OR13, -(C,-Cg alkylene)SR13, -(Ci-Cg alkylene)S(O)2R13, -(Ci-Cg alkylene)S(O)2NR14R15, -(Ci-Cg alkylene)NR13S(O)2R14, -(Ci-Cg alkylene)NR14R15, -(Ci-Cg alkylene)C(O)R13, -(Ci-C6alkylene)NR13C(O)R14, -(Ci-Cg alkylene)NR13C(O)NR14R15, -(Ci-C6alkylene)C(O)OR13, -(Ci-C6alkylene) C(O)ONR14R15, or -(Ci-C6alkylene)-C(O)NR14R15, wherein each is independently optionally substituted with Rd; each Rdis independently selected from about the group consisting of halogen, -OH, oxo, -CN, Ci- G, haloalkyl, Ci-Ce alkoxy, Ci-C-6 haloalkoxy, -COOH, and Ci-Ce alkyl optionally substituted with -OH, halogen, CN, or oxo; each R10, R11, andR12is independently hydrogen, Ci-Q, alkyl, C2-C6 alkenyl, C2-C6 alkynyl, Cs-Cg cycloalkyl, -(Ci-Cs alkylene)C3-Cf, cycloalkyl, 3- to 6-membered heterocyclyl, or -(Ci-Cr, alkylene)3- to 6-membered heterocyclyl, wherein each of R10, R11and R12is independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, Cj-G, alkoxy, or Ci-Ce alkyl optionally substituted by oxo, -OH, or halogen; or R11andR12are taken together with the atom(s) to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halogen, or Ci-G, alkyl optionally substituted by oxo, -OH, or halogen; each R13, R14and R15is independently hydrogen, Ci-Ce alkyl, C2-C.6 alkenyl, C2-C6 alkynyl, Ci-Ce haloalkyl, C3-C6 cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each of R10, R11, andR12is independently optionally substituted by oxo, -OH, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, or G-G, alkyl optionally substituted by oxo, -OH, or halogen; or R14and R15are taken together with the atoms to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halogen, or Ci-Cr, alkyl optionally substituted by oxo, -OH, or halogen; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4; provided that when Z is -NRcS(O)2CH3, -CONH2 or -C(O)OH, G is a bond, and t is 1, then L is not a bond.

[0085] In certain embodiments, the compound is not l -[7-(4-bromo-2,6-dimethylphenyl)-2,5-dimethyl- 7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-azetidinebutanoic acid, l-[7-(4-bromo-2,6-dimethylphenyl)-2,5- dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-3-azetidinepentanoic acid, or N-((l -(6-fluorobenzo[d]oxazol- 2-yl)azetidin-3-yl)methyl)-N-methylacetamide.

[0086] In some embodiments, A is hydrogen. In some embodiments, A is Ci-Ce alkyl. In some embodiments, A is methyl. In some embodiments, A is Ci-Ce alkyl optionally substituted by halogen. In some embodiments, A is -CF3. In some embodiments, A is Ce-aryl. In some embodiments, A is phenyl.

[0087] In some embodiments, G is a bond. In some embodiments, G is -CH2-. In some embodiments, G is -CH2-CH2-.[0088J In some embodiments, Raand Rbare independently hydrogen or Ci-Cs alkyl. In some embodiments, Raand Rbboth are hydrogen. In some embodiments, any one of Raand Rbis hydrogen and other is Ci-Ce alkyl. In some embodiments, Raand Rbboth are Ci-Cg alkyl. In some embodiments, any one of Raand Rbis hydrogen and other is methyl. In some embodiments, any one of Raand Rbis hydrogen and other is ethyl. In some embodiments, Raand Rbboth are methyl.[00891 In some embodiments, Raand Rbare taken together with the atoms to which they attached to form a C3-C6 cycloalkyl ring. In some embodiments, Raand Rbare taken together with the atoms to which they attached to form a cyclopropyl ring.

[0090] In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl. In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclobutyl ring. In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclopentyl ring. In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclohexyl ring.

[0091] In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring, in such case the other one of Raor Rbis hydrogen. In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclobutyl ring, in such case the other one of Raor Rbis hydrogen. In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclopentyl ring, in such case the other one of Raor Rbis hydrogen. In some embodiments, any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclohexyl ring, in such case the other one of Raor Rbis hydrogen.

[0092] In some embodiments, G is a bond, -CH2- or -CH2-CH2-; and any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring. In some embodiments, G is -CH2-; and any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclobutyl ring. In some embodiments, G is -CH2-; and any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclopentyl ring. In some embodiments, G is -CH2-CH2-; and any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclohexyl ring.[00931 In some embodiments, L is a bend, or Ci-Ce alkylene or C2-C6 alkenylene. The Ci-Cr, alkylene or C2-C6 alkenylene can be linear or branched. In some embodiments, L is a bond. In some embodiments, L is a Ci-Ce alkylene. In some embodiments, L is -CH2-. In some embodiments, L is-C2H4-. In some embodiments, L is -C3H6-. In some embodiments, L is -CH(CH3)-. In some embodiments, L is -C(CH3)2-. In some embodiments, L is -CH(CH3)-CH2-. In some embodiments, L is-CH2-CH(CH3)-. In some embodiments, L is -C(CdlO’-CII’-. In some embodiments, L is -C'lli-C(CIl-)’-. In some embodiments, L is -CH(C2H5)-CH2-.

[0094] In some embodiments, L is a C2-Ce alkenylene. The C2-Ce alkenylene can be linear or branched. In some embodiments, L is a -CH=CH-. In some embodiments, L is -CH2-CH=CH-.

[0095] In some embodiments, t is 0 or 1. In some embodiments, t is 0. In some embodiments, t is 1.

[0096] In some embodiments, when t is 0 then Raand Rbare absent and L is G-G> alkenylene. In some embodiments, when t is 0 then Raand Rbare absent and L is -CH=CH-.

[0097] In some embodiments, when t is 1 then Raand Rbare present and L is a bond or Ci-Cs alkylene. In some embodiments, when t is 1 then Raand Rbare present and L is a bond. In some embodiments, when t is 1 then Raand Rbare present and L is G-Cg alkylene. In some embodiments, when t is 1 then Raand Rbare present and L is -CH2-. In some embodiments, when t is 1 then Raand Rbare present and L is -CH2-CH2-. Wherein Raand Rbare independently selected from about hydrogen or Ci-Ce alkyl.

[0098] In some embodiments, when t is 1 then Raand Rbare present and any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring, in such case other one of Raor Rbis hydrogen. In some embodiments, when t is 1 then Raand Rbare present and any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a cyclobutyl ring, in such case other one of Raor Rbis hydrogen.

[0099] In some embodiments, Z is selected from about -NRCSO2NH2, -NRCS(O)2CH3, -SO2NH2, -NRCC(O)CH3, -C(O)OH, -CONH2, NRCCONH2, -CONH(OH), -B(OH)2, -P(O)(OH)2, -SO2OH, -NRCS(O)2CF3, -NRCS(O)2NHCH3, or-NRcCH2C6-aryl-S(O)2NH2. In some embodiments, Z is -NRCS(O)2NH2. In some embodiments, Z is -NRCS(O)2CH3. In some embodiments, Z is -SO2NH2. In some embodiments, Z is -NRCC(O)CH3. In some embodiments, Z is -C(O)OH. In some embodiments, Z is -CONH2. In some embodiments, Z is -NRCCONH2. In some embodiments, Z is -CONH(OH). In some embodiments, Z is -B(OH)2. In some embodiments, Z is -P(O)(OH)2. In some embodiments, Z is -SO2OH. In some embodiments, Z is -NRCS(O)2CF3. In some embodiments, Z is -NRCS(O)2NHCH3. In some embodiments, Z is -NRcCH2C6-aryl-S(O)2NH. In some embodiments, Rcis selected from about hydrogen, Ci-Cg alkyl, G-G, cycloalkyl or Ci-Cg haloalkyl. In some embodiments, Rcis methyl. In some embodiments, Rcis ethyl. In some embodiments, Rcis isopropyl. In some embodiments, Rcis n-propyl. In some embodiments, Rcis cyclopropyl. In some embodiments, Rcis cyclobutyl. In some embodiments, Rcis cyclopentyl. In some embodiments, Rcis. In some embodiments, Rcis F . In some embodiments,[01001 In some embodiments, Rcis -(Ci-Cf, alkyl cne)C--Cf cycloalkyl optionally substituted with Rd. In some embodiments, Rcis 3- to 6-membered heterocyclyl optionally substituted with Rd. In some embodiments, Rcis -(Ci-Cg alkylene)3- to 6-membered heterocyclyl optionally substituted with Rd. In some embodiments, Rcis -(Ci-Cf alkylene)C6-aryl optionally substituted with Rd. In some embodiments, Rcis 5- to 6-membered heteroaryl optionally substituted with Rd. In some embodiments, Rcis-(Ci-Cf, alkylene)5- to 6-membered heteroaryl optionally substituted with Rd. In some embodiments, Rcis -(Ci-Cf, alkylene)OR13. In some embodiments, Rcis -(Ci-Cf alkylene)SR13. In some embodiments, Rcis -(Ci-Ce alkylene)S(O)2R13. In some embodiments, Rcis -(Ci-Cg alkylene)S(O)2NR14R15. In some embodiments, Rcis -(Ci-Cg alkylene)NR13S(O)2R14. In some embodiments, Rcis -(Ci-Ce alkylene)NR14R15. In some embodiments, Rcis -(Ci-Cf, alkylene)C(O)R13. In some embodiments, Rcis -(Ci-Ce alkylene)NR13C(O)R14. In some embodiments, Rcis -(Ci-Ce alkylene)NR13C(O)NR14R15. In some embodiments, Rcis -(Ci-Cf, alkylene )C(O)OR13. In some embodiments, Rcis -(Ci-Ce alkylene) C(O)ONR14R13. In some embodiments, Rcis -(Ci-Cf, alkylene)-C(O)NR14R13.10101] In some embodiments, -Ci-Cf alkylene of any Rcgroup may be optionally substituted with Rd.

[0102] In some embodiments, -Ci-Ce alkylene of any Rcgroup is linear or branched.

[0103] In some embodiments, Rcis selected from about the group consisting of methyl, ethyl, isopropyl,NHSO2NH2

[0104] In some embodiments, Z is selected from about the group consisting ofwherein wavy lines denote the attachment points.[0105| In some embodiments, Z is -NRCSO2NH2.OxX / 0VS'NH2|[0106) In some embodiments, Z is -NHSO2NH2. In some embodiments, Z is . In someA ° ° F embodiments, Z is. , . In some embodiments, Z PF3CX / N°AVNH2 is. In some embodiments, Z is W, . In some embodiments, Z is.. .In some embodiments, Z is . In some embodiments, Z is

[0107] In some embodiments, Z is -NHS(O)2CH3.

[0108] In some embodiments, Z is -SO2NH2.

[0109] In some embodiments, Z is -NHC(O)CH3.

[0110] In some embodiments, Z is -C(O)OH.10111] In some embodiments, Z is -CONH2

[0112] In some embodiments, Z is -NHCONH2

[0113] In some embodiments, Z is -CONH(OH).

[0114] In some embodiments, Z is -B(OH)2.

[0115] In some embodiments, Z is -P(O)(OH)2.

[0116] In some embodiments, Z is -S(O)2OH.10117] In some embodiments, Z is -NRcS(O)2CF3.

[0118] In some embodiments, Z is -NRCS(O)2NHCH3.

[0119] In some embodiments, Z is -NRcCH2C6-aryl-S(O)2NH2.

[0120] In some embodiments, Z is -NHCH2C6-aryl-S(O)2NH2.

[0121] In some embodiments, Z is -N(CH3)CH2C6-aryl-S(O)2NH2.

[0122] In some embodiments, G, Ra, Rb, L, t and Z together is selected from about the group consisting, y p .

[0123] In some embodiments, when any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring then L and Z together is selected from about, wherein wavy lines denote the attachment points.101241 In some embodiments, when any one of Raand Rb, and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring then L and Z together is selected from aboutNH2H0''VyF F , wherein wavy lines denote the attachment points.

[0125] In some embodiments, when any one of Raand Rb, and A arc taken together along with the atoms to which they are attached to form a cyclobutyl ring (which forms with the azetidine an azaspiroheptane oring) then L and Z together is selected from about the group consisting of, , wherein wavy lines denote the attachment points.

[0126] In some embodiments, Ring C is 5- to 6-membered heteroaryl optionally substituted with R1. In embodiments, Ring C is 5-membered heteroaryl optionally substituted with R1. In some embodiments, Ring C is 6-membered heteroaryl optionally substituted with R1. In some embodiments, Ring C is selected from about the group consisting of imidazole, pyrazole, pyrrole, pyridine, pyrimidine, pyridone, pyrimidone, pyridazine, pyridazinone, and triazine, wherein each of which is optionally substituted with R1. In some embodiments, the R1is selected from about hydrogen, oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C;-C< cycloalkyl, 3- to 6-membered heterocyclyl, Ce-aryl, 5- to 6-membered heteroaryl, -CN, -CONR1'R12, or -NR”R12, wherein each of which is optionally substituted by R9. In some embodiments, the R1is selected from about hydrogen, oxo, methyl, ethyl, ethylene, propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantly, oxetanyl, tetrahydropyranyl, pyrazolyl, pyridyl, pyrimidyl, phenyl, -CONH2, -NH2, -CHF2, -CF3, -Cl, and -CN; wherein each of which is optionally further substituted with pyridyl, -F, -CF3, or -CHF2.

[0127] In some embodiments, Ring D is G,-aryl or 5- to 6-membered heteroaryl, each of which is optionally substituted with R2; wherein Ring D is fused to Ring C. In some embodiments, Ring D is G- aryl optionally substituted with R2; wherein Ring D is fused to Ring C. In some embodiments, Ring D is 5- to 6-membered heteroaryl optionally substituted with R2; wherein Ring D is fused to Ring C. In some embodiments, Ring D is 5-membered heteroaryl optionally substituted with R2; wherein Ring D is fused to Ring C. In some embodiments, Ring D is 6-mcmbcrcd hctcroaryl optionally substituted with R2; wherein Ring D is fused to Ring C. In some embodiments, Ring D is selected from about the group consisting of phenyl, pyrrole, pyrazole, imidazole, pyridine, thiophene, and pyrimidine optionally substituted with R2; wherein each of which is fused to Ring C. In some embodiments, R2is selected from about hydrogen, halogen, oxo, G-G, alkyl, Ci-Ce alkoxy, C3-C6 cycloalkyl, -OR10, -CN, and Ce-aryl; wherein each of which is optionally substituted by R9. In some embodiments, R2is selected from abouthydrogen, fluorine, bromine, chloro, oxo, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, phenyl, 4- methoxypheyl, -CN, -OCH2F, -OCH2OCH3, -(OCH2CH2)morpholine, 4-hydroxycyclohexyl, -CF3, cyclopropyl, and phenyl.

[0128] In some embodiments, any two of R2are taken together with the atoms to which they attached to form a Cs-Cr, cycloalkyl, 5- to 6-membered heterocyclyl, Ce-aryl, or 5- to 6-membered heteroaryl, wherein each of which is optionally substituted by R9. In some embodiments, any two of R2are taken together with the atoms to which they attached to form imidazole, dioxole and dihydro dioxine, wherein each of which is optionally substituted with methyl.

[0129] In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0130] In some embodiments, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0131] In some embodiments, Ring C, Ring D, R1, and R2together is selected from about the group consisting of:lines denote the attachment points.

[0132] In some embodiments, Ring C, Ring D, R1, and R2together is selected from about the group consisting of:

[0133] It is understood that each description of A, G, Ra, Rb, L, Z, Ring C, Ring D, R1, R2, Rc, m, n, and t may be independently combined with each description of A, G, Ra, Rb, L, Z, Ring C, Ring D, R1, R2, Rc, m, n, and t the same as if each and every combination were specifically and individually listed.

[0134] In certain embodiments, the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof:Table 1

[0135] In certain embodiments, the compound is Compound II:or a pharmaceutically acceptable salt thereof.

[0136] In certain embodiments, the compound is Compound 111:or a pharmaceutically acceptable salt thereof.

[0137] In certain embodiments, the compound is Compound IV:or a pharmaceutically acceptable salt thereof.

[0138] In certain embodiments, the compound is Compound V :or a pharmaceutically acceptable salt thereof.

[0139] In certain embodiments, the compound is Compound VI:or a pharmaceutically acceptable salt thereof.

[0140] In certain embodiments, the compound is Compound VII:or a pharmaceutically acceptable salt thereof.10141] In certain embodiments, the compound is Compound VIII:or a pharmaceutically acceptable salt thereof.

[0142] In certain embodiments, the compound is Compound IX:or a pharmaceutically acceptable salt thereof.

[0143] In certain embodiments, the compound is Compound X:or a pharmaceutically acceptable salt thereof.10144] In certain embodiments, the compound is Compound XI:or a pharmaceutically acceptable salt thereof.10145] In certain embodiments, the compound is Compound XII:or a pharmaceutically acceptable salt thereof.

[0146] In certain embodiments, the compound is Compound XIII:or a pharmaceutically acceptable salt thereof.

[0147] In certain embodiments, the compound is a compound disclosed in W02022091048A1,US20220135598A1, US20240352046A1, WO2021226136A1, US20230190927A1, W02023035001A1, US20240374724A1, W02023077083A1, US20230002387A1, W02023220402A1, W02023109909A1, WO2023143520A1, WO2024074128A1, US20220411420A1, WO2023242631 Al, WO2019046778A1, US20200291024A1, US20230183239A1, WO2019177971A1, US20190282703 Al, W02019191504A1, US20210023234A1, W02021061803A1, W02020140001 Al, US20220056052A1, W02020210649A1, US20220362266A1, WO2022197734A1, WO2022212488A1, WO2024148272A1, WO2021133915A1, WO2024149239A1, WO2024199444A1, CN115536696A, WO2023197987, WO2024028727A1, WO2024127343 Al, US20230103498A1, WO2019051269A1, US20210369747A1, US20230103498A1, US20230277570A1, US20220289775A1, US20190031655A1, WO2019023635 Al, US20200039979A1, W02020028724A1, US20200299258A1, W02020190912A1, WO2021158829A1, US20210253556A1, US20230183212A1, WO2022119928A1, WO2021225407A1, US20230159469A1, WO2022146022A1, US20240140944A1, WO2022164249A1, US20240116882A1, US20230270767A1, WO2021225954A1, US20220033512A1, W02022056068A1, WO2021231726A1, US20230183188A1, WO2023086638A1, WO2023225001 Al, WO2021225969A1, WO2021257614A1, US20230036933A1, US20240376113A1, US2025 / 0101019A1, W02025 / 007955A1, WO2025 / 026377A1, WO2025 / 026383A1, or Gangar, et al.,Bioorganic Chemistry, Volume 119, February 2022, 105549 (e.g., compound 43), or a pharmaceutically acceptable salt thereof.

[0148] In certain embodiments, the compound is ISM5939, SR-8541A, MV-626, TXN10128, ZX-8177, STF-1623, or RBS2418, or a pharmaceutically acceptable salt thereof.

[0149] In certain embodiments, the compound is selected from Table A, or a pharmaceutically acceptable salt thereof:Table ACompositions

[0150] The present disclosure also provides pharmaceutical compositions. Such compositions include a pharmaceutically effective amount of a compound provided herein, and a pharmaceutically acceptable carrier.

[0151] Tire term “pharmaceutically acceptable” component is one that is suitable for use with humans and / or animals without undue adverse side effects (such as toxicity, irritation, and allergic response) commensurate w ith a reasonable benefit / risk ratio. Further, a “pharmaceutically acceptable carrier” will generally be a non-toxic solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.

[0152] The term “carrier” refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions. Suitable pharmaceutical excipients include starch,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents such as acetates, citrates or phosphates. Antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid: and agents for the adjustment of tonicity such as sodium chloride or dextrose are also envisioned.

[0153] In certain embodiments, the compounds or compositions provided herein is administered to a subject orally.

[0154] Depending on the intended mode of administration, the disclosed compounds or compositions can be in solid or semi-solid form, such as, for example, tablets, pills, time-release capsules, elixirs, tinctures, emulsions, gelcap. syrups, powders, gel or the like, sometimes in unit dosages and consistent with conventional pharmaceutical practices. The composition can be formulated as a suppository, with traditional binders and carriers such as triglycerides.

[0155] Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by E. W. Martin, incorporated herein by reference. Such compositions will contain a therapeutically effective amount of the antigen-binding polypeptide, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration. The parental preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0156] Illustrative pharmacal compositions are tablets and gelatin capsules comprising a compound of the disclosure and a pharmaceutically acceptable carrier, such as a) a diluent, e.g., purified water, triglyceride oils, such as hydrogenated or partially hydrogenated vegetable oil, or mixtures thereof, com oil, olive oil, sunflower oil, safflower oil, fish oils, such as EPA or DHA, or their esters or triglycerides or mixtures thereof, omega-3 fatty acids or derivatives thereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, sodium, saccharin, glucose and / or glycine; b) a lubricant, e.g.. silica, talcum, stearic acid, its magnesium or calcium salt, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and / or polyethylene glycol; for tablets also; c) a binder, e.g.. magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesium carbonate, natural sugars such as glucose or beta-lactose, com sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, waxes, and / or polyvinylpyrrolidone, if desired; d) a disintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthan gum, algic acid or itssodium salt, or effervescent mixtures; e) absorbent, colorant, flavorant and sweetener; f) an emulsifier or dispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 90, labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex 355, gelucire, vitamin E TGPS or other acceptable emulsifier; and / or g) an agent that enhances absorption of the compound such as cyclodextrin, hydroxypropyl-cyclodextrin, PEG400, PEG200.

[0157] Pharmaceutical dosage forms of a compound of this disclosure may be manufactured by any of the methods well-known in the art, such as, for example, by conventional mixing, sieving, dissolving, melting, granulating, dragee-making, tableting, suspending, extruding, spray-drying, levigating, emulsifying, (nano- / micro-) encapsulating, entrapping, or lyophilization processes. As noted above, the compositions of this disclosure can include one or more physiologically acceptable inactive ingredients that facilitate processing of active molecules into preparations for pharmaceutical use.

[0158] In certain embodiments, the compositions are comprised of a compound of this disclosure in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the claimed compounds. Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

[0159] Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semi-solid excipients may be selected from about glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. In some embodiments, liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

[0160] Compressed gases may be used to disperse a compound of this disclosure in an aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipients and their formulations are described in Remington’s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).

[0161] The compositions of this disclosure may, if desired, be presented in a pack or dispenser device containing one or more unit dosage forms containing the active ingredient. Such a pack or device may, for example, comprise metal or plastic foil, such as a blister pack, or glass, and rubber stoppers such as in vials. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of this disclosure that can be formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0162] The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of this disclosure based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. In one embodiment, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical fonnulations are described below.Methods of Treatment

[0163] The present disclosure provides a method of treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or Table 1 (e.g., Compound II) or a pharmaceutically acceptable salt thereof, or a composition as provided herein.

[0164] Provided herein are use of a therapeutically effective amount of a compound of Formula I or Table 1 (e.g., Compound II), or a composition in the manufacture for a medicament for treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof.

[0165] Also provided herein is a therapeutically effective amount of Formula I or a compound of Table 1 (e.g., Compound II or a composition for use in the treatment or prevention of one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof.

[0166] In some embodiments, the subject is an infant, a child, an adolescent or an adult.

[0167] In some embodiments, the subject is 1) a treatment naive subject: 2) an adult with childhoodonset HPP: 3) an adult with adult-onset HPP; 4) a juvenile with childhood-onset HPP; 5) an infant with infantile HPP; or 6) an enzyme replacement therapy (EZRT) intolerant subject.

[0168] Tire terms "hypophosphatasia " or “HPP,” as used herein, refer to a rare, heritable skeletal disorder caused by, e.g., one or more loss-of-function mutations in tire ALPL (alkaline phosphatase, liver / bone / kidney) gene, which encodes tissue-nonspecific alkaline phosphatase (TN SALP). HPP may be further characterized as perinatal HPP (e.g.. benign perinatal HPP or lethal perinatal HPP), infantile HPP. childhood HPP, adult HPP or odonto-HPP. See Michigami et al., Clin Pediatr Endocrinol, 2020.

[0169] For instance, “perinatal HPP” presents with clinical features noted either at birth or in utero based on prenatal ultrasound. Clinical exam reveals obvious skeletal abnormalities including chest wall deformities, as well as long bones that are short or bowed or both. The skeleton is hypomineralized. Historically, this form of HPP was frequently fatal. However, the availability of alkaline phosphatase enzyme replacement therapy (asfotase alfa) has significantly altered the natural history of perinatal HPP and most children survive.

[0170] ‘ ‘Infantile HPP” describes a patient having HPP that is less than 6 months of age after birth. Characteristic changes of rickets are seen on radiographs, and fractures are often present. Infants fail to grow appropriately and some experience vitamin B6-responsive seizures. Hypercalcemia andnephrocalcinosis also are common. As with the perinatal form, morbidity and mortality are attenuated with asfotase alfa treatment.

[0171] “Childhood HPP / juvenile HPP” describes a patient having HPP that is after 6 months of age to about 18 years of age. Children often have delays in gross motor milestones and static myopathy. A common feature of childhood HPP is premature loss of deciduous teeth (before 5 years of age) with the roots intact. Radiographs reveal changes consistent with rickets and often a radiolucent band extending from the growth plate into the metaphysis.

[0172] “Adult HPP” describes a patient having HPP that is older than about 18 years of age. Adult HPP may manifest with recurrent or slow-to-heal metatarsal fractures or subtrochanteric femoral pseudofractures. A review of Mayo Clinic patients diagnosed with HPP as adults demonstrated that nonspecific musculoskeletal complaints were common at the time of presentation. Many adults with HPP report having had symptoms during childhood, despite formal diagnosis not being made until later in life.

[0173] ‘ Odonto-HPP” is the least severe form of HPP regardless of age. Odontohypophosphatasia is diagnosed w hen dental abnormalities are present but no other skeletal disease, such as rickets or osteomalacia, is identified.

[0174] In some embodiments, the hypophosphatasia is prenatal hypophosphatasia. In some embodiments, the hypophosphatasia is perinatal hypophosphatasia.

[0175] By “treatment naive subject” is meant a subject or patient having HPP that has never received a treatment of medicine or therapy for HPP. In other words, prior to the treatment using the compound or composition provided herein, the subject has not received any prior treatment or therapy for HPP.

[0176] By “adult with childhood-onset HPP” is meant an adult subject or patient suffering from HPP with the onset of the HPP at childhood or the time of being a juvenile.

[0177] By “adult with adult-onset HPP” is meant an adult subject or patient suffering from HPP with the onset of the HPP at the time of being an adult.

[0178] By “juvenile with childhood-onset HPP” is meant an adolescent or a child subject or patient suffering from HPP with the onset of the HPP at childhood or the time of being a juvenile.

[0179] By “infant with infantile HPP” is meant an infant subject or patient suffering from HPP with the onset of the HPP at infancy.

[0180] In certain embodiments, prior to the treatment using the compound or composition provided herein, the subject has received a prior treatment or therapy for HPP, such as enzyme replacement therapy (EZRT), for example Strensiq®.

[0181] In certain embodiments, the subject is refractory' to, or has relapsed following a prior treatment for HPP, such as EZRT (for example Strensiq®).

[0182] In certain embodiments, the subject is EZRT intolerant or EZRT resistant.

[0183] In some embodiments, the hypophosphatasia is of any form. In some embodiments, the one or more symptoms of HPP include at least one of pathogenic or likely pathogenic ALPL gene mutation, elevated blood and / or urine levels of natural substrates, poorly healing fractures, chondrocalcinosis, nephrocalcinosis, rickets, early atraumatic loss of teeth, premature loss of deciduous teeth, short stature or linear growth failure overtime, delayed motor milestones, craniosynostosis. B6 responsive seizures, incomplete bone mineralization, elevated blood and / or urine levels of inorganic pyrophosphate (PPi), elevated blood levels of phosphoethanolamine (PEA), elevated urine levels of PEA, elevated blood levels of pyridoxal 5 ’-phosphate (PLP), elevated urine levels of PLP, hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture (such as atypical femoral fractures or recurrent metatarsal fractures), HPP-related seizure, inadequate weight gain, calcium pyrophosphate dihydrate crystal deposition, or any combinations thereof.

[0184] The one or more symptoms of EIPP selected from about Table 2 can be used in the diagnosis of HPP in adults and children with persistently low alkaline phosphatase (ALP). The diagnostic criteria are described in the prior art, such as by Khan et al., Osteoporosis International, 2023, 35:431-438 (illustrated in Table 2), which is hereby incorporated by reference in its entirety.Table 2. Diagnostic Criteria for HPP in Adults and Children with Persistently Low ALP

[0185] In some embodiments, the subject has an alteration in the ALPL gene. In some embodiments, the alteration in the ALPL gene is a mutation. In some embodiments, the subject has an alteration in a gene that can regulate TN SALP activity. In some embodiments, the alteration in a gene that can regulate TN SALP activity is an alteration in RUNX2.

[0186] Subjects having HPP can be identified for treatment with the compounds or compositions provided herein by determining the Inorganic pyrophosphate (PPi) and / or Pyridoxal 5 ’-Phosphate (PLP) concentrations in a plasma sample from about the subject. PPi plays a critical role in various biological processes, including bone mineralization and energy metabolism. Tire physiological levels of PPi can vary in the body, notably in plasma and urine, and can be influenced by several factors, including health conditions such as hypophosphatasia (HPP). In patients with HPP, plasma and urine levels of PPi are elevated due to the reduced enzymatic activity of ALP.

[0187] Any method known to those of skill in the art can be used to quantify the PPi and PLP concentrations in a plasma sample or alternatively in a urine sample, as described in detail in Whyte et al., 1995 (J. Clin. Invest. 95(4): 1440-1445), hereby incorporated by reference in its entirety . In particular, PPi and PLP concentrations in a plasma sample can be used to evaluate ALP activity for the patient. In comparison to healthy subjects (e.g., healthy subjects of about the same age, same gender, and / or same height), HPP patients typically exhibit elevated plasma concentrations of PPi and PLP, such as a PPi concentration of about 5 pM or greater and / or a PLP concentration of about 50 ng / ml or greater. Thelower normal limit for plasma PPi concentrations of healthy adults is about 1 pM, while the upper normal limit is about 5.9 pM. Tire lower normal limit for plasma PPi concentrations of adolescent adults is about 0.8 pM, while the upper normal limit is about 4.9 pM. The urinary PPi concentration can vary more widely than plasma levels, but in general, the daily excretion in a healthy adult is approximately 10-15 mg / day, depending on various factors like diet and hydration status. Tire lower normal limit for plasma PLP concentrations of healthy adults is less than about 10 ng / ml, while the upper normal limit is about 60 ng / ml. The lower normal limit for plasma PLP concentrations of adolescent adults is less than about 10 ng / ml, while the upper normal limit is less than about 25 ng / mL.

[0188] In certain embodiments, the methods of the present disclosure result in a decrease of urine or plasma levels of inorganic pyrophosphate (PPi) in tire subject having or being prone to HPP. Prior to the administration, the subject has a plasma PPi concentration of about 4.5 pM or greater. In certain embodiments, the methods result in an increase of urine or plasma levels of enzyme alkaline phosphatase (ALP) in the subject having or being prone to HPP. For example, treatment with the compound or composition provided herein results in a decrease in PPi concentration in a sample (e.g., a plasma sample or a urine sample) from about the patient of about 1 pM. about 1.5 pM, about 2 pM, about 2.5 pM, or about 3 pM, about 4 pM, about 5 pM, about 6 pM, about 7 pM, about 8 pM, about 9 pM, about 10 pM, about 15 pM, or about 20 pM. or at least about 10% (e.g., at least about 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%. 70%. 75%. 80%. 85%. 90%. or 95%). Thus, the subject exhibits a plasma or urine PPi concentration of, e.g., about 2 pM to about 5 pM, about 3 pM to about 5 pM, about 2 pM to about 4 pM, about 2 pM to about 3 pM, or about 1 pM to about 3 pM after administration of the compound or composition provided herein. In certain embodiments, treatment with the compound or composition provided herein results in a decrease in PPi concentration in a urine sample from about the patient of about 1-3 mg / day. about 1-5 mg / day, about 2-8 mg / day. about 2-10 mg / day, about 5-10 mg / day. or at least 10% (e.g.. at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%. 60%. 65%. 70%, 75%, 80%, 85%, 90%, or 95%. Thus, the subject exhibits a urine PPi concentration of, e.g., about 2 mg / day to about 5 mg / day, about 3 mg / day to about 8 mg / day, about 2 mg / day to about 8 mg / day, about 5 mg / day to about 10 mg / day, or about 5 mg / day to about 15 mg / day after administration of tire compound or composition provided herein.

[0189] PLP is the active form of vitamin B6 and serves as a coenzyme in numerous biochemical reactions, including those involved in amino acid metabolism, neurotransmitter synthesis, and glycogenolysis. Normally, ALP converts PLP to pyridoxal (PL), which can then cross cell membranes easily. In HPP, due to the deficiency of ALP, PLP accumulates outside of cells because it cannot be adequately dephosphory lated to PL. This accumulation can lead to a biochemical imbalance, as PLP is essentially trapped in its phosphorylated form and cannot be utilized effectively in the body. The elevatedlevels of PLP in the serum are often used as one of the biochemical markers for diagnosing HPP. It's noteworthy that despite the high levels of PLP, individuals with HPP do not typically exhibit symptoms of vitamin B6 excess. This paradoxical situation is due to the enzyme deficiency at the root of HPP, which prevents the proper utilization of PLP within the body’s biochemical pathways.

[0190] In certain embodiments, treatment of the compounds or compositions provided herein results in an average decrease in PLP concentrations in a plasma sample and / or urine sample from about the patient of at least about 10% (e.g., at least 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%) relative to PLP concentrations in a plasma sample from about the patient prior to administration of the compounds or compositions provided herein.

[0191] Alkaline phosphatase (ALP) is an enzyme found in various tissues throughout the body, including the liver, bones, kidneys, and bile ducts. ALP plays a critical role in the process of breaking down proteins and is also involved in dephosphorylation, where phosphate groups are removed from about molecules, including the breakdown of inorganic pyrophosphate (PPi). The normal range of ALP can van depending on several factors, including age, sex, and the specific assay methods used by different laboratories. In adults, the normal range for ALP levels in the blood is usually cited as approximately 30 to 120 units per liter (U / L), but these values can vary based on the laboratory's reference standards. Children and adolescents typically have higher levels due to bone growth, and levels can also vary during pregnancy. ALP can also be measured in the urine, where it is normally present in low amounts. Urinary ALP levels can increase in conditions that affect the kidneys, but there isn't a well-established "normal" range like there is for plasma ALP levels. Prior to the administration, the subject has a plasma ALP concentration of about 90 U / L or less for a subject of 0 to 14 days of age; about 34 U / L or less for a subject of 15 days of age to less than 1 year of age; about 156 U / L or less for a subject of about 1 year of age to less than 10 years of age; about 141 U / L or less for a subject of about 10 years of age to less than about 13 years of age; about 62 U / L or less for a female subject of about 13 years of age to less than about 15 years of age; about 127 U / L or less for a male subject of about 13 years of age to less than about 15 years of age; about 54 U / L or less for a female subject of about 15 years of age to less than about 17 years of age; about 89 U / L or less for a male subject of about 15 years of age to less than about 17 years of age; about 48 U / L or less for a female subject of about 17 years of age or older; or about 59 U / L or less for a male subject of about 17 years of age or older.

[0192] Treatment with the compound or composition provided herein results in an increase in ALP concentration in a sample (e.g., a plasma sample or a urine sample) from about a subject (e.g., a human) having or being prone to HPP of at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%, or at least about 100 U / L or greater, relative to the subject prior to administration of the compound or composition provided herein. For example, administration ofthe compound or composition provided herein increases the ALP concentration in a sample (e.g., a plasma sample) from about the subject to, e.g, about 1 U / L or greater for a subject of 0 to 14 days of age; about 518 U / L or greater for a subject of 15 days of age to less than 1 year of age; about 369 U / L or greater for a subject of about 1 year of age to less than 10 years of age; about 460 U / L or greater for a subject of about 10 years of age to less than about 13 years of age; about 280 U / L or greater for a female subject of about 13 years of age to less than about 15 years of age; about 517 U / L or greater for a male subject of about 13 years of age to less than about 15 years of age; about 128 U / L or greater for a female subject of about 15 years of age to less than about 17 years of age; about 365 U / L or greater for a male subject of about 15 years of age to less than about 17 years of age; about 95 U / L or greater for a female subject of about 17 years of age or older; or about 164 U / L or greater for a male subject of about 17 years of age or older.

[0193] In certain embodiments, the composition provided herein containing the compounds described herein are administered for prophylactic and / or therapeutic treatments. In certain therapeutic applications, the compounds are administered to a patient already suffering from about a disease or disorder, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of a healthcare practitioner. Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and / or dose ranging clinical trial.

[0194] In prophylactic applications, the compounds provided herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a “prophylactically effective amount or dose.” In this use, the precise amounts also depend on the patient’s state of health, weight, and the like. When used in patients, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient’s health status and response to the drags, and the judgment of a healthcare professional. In one aspect, prophylactic treatments include administering to a patient, who previously experienced at least one symptom of the disease being treated and is currently in remission, a composition provided herein comprising a compound described herein, or a pharmaceutically acceptable salt thereof, in order to prevent a return of the symptoms of the disease or condition.

[0195] Dosages of compositions or compounds provided herein can be provided in either a single or multiple dosage regimens. Doses can be administered, e.g., hourly, bihourly, daily, bidaily, twice a week, three times a week, four times a week, five times a week, six times a week, weekly, biweekly, monthly, bimonthly, or yearly. Alternatively, doses can be administered, e.g., twice, three times, four times, five times, six times, seven times, eight times, nine times, 10 times, 11 times, or 12 times per day. Inparticular, the dosing regimen is once weekly. The duration of the dosing regimen can be, e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 day(s), week(s), or month(s), or even for the remaining lifespan of the HPP patient, such as an infant having HPP (infant HPP, e.g ., an infant of about 3 years of age or less than 3 years of age), a child having HPP (child HPP, e.g., a child of about 5 to about 12 years of age), an adolescent having HPP (juvenile HPP or adolescent HPP. e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (adult HPP, e.g., an adult having HPP older than about 18 years of age. The amount, frequency, and duration of dosage will be adapted by the clinician in accordance with conventional factors such as the extent of the disease and different parameters from about the HPP patient, such as an infant having HPP (e.g., an infant of about 3 years of age or less than 3 years of age), a child having HPP (e.g., a child of about 5 to about 12 years of age), an adolescent having HPP (e.g., an adolescent having HPP of about 12 to about 18 years of age) or an adult having HPP (e.g., an adult having HPP older than about 18 years of age.

[0196] In certain embodiments wherein tire patient’s condition does not improve, upon the discretion of a healthcare professional the administration of the composition provided herein are administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0197] In certain embodiments wherein a patient’s status does improve, the dose of drug being administered is temporarily reduced or temporarily suspended for a certain length of time (z.e., a “drug holiday”). In specific embodiments, the length of the drug holiday is between 2 days and 1 year, including by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days, or more than 28 days. Tire dose reduction during a drug holiday is, by way of example only, by 10%- 100%, including by way of example only 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%. 75%. 80%. 85%. 90%. 95%. and 100%.

[0198] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, in specific embodiments, the dosage or the frequency of administration, or both, is reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. In certain embodiments, however, the patient requires intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0199] The amount of a given agent that corresponds to such an amount varies depending upon factors such as the particular compound, disease condition and its severity, the identity e.g., weight, sex) of the subject or host in need of treatment, but nevertheless is determined according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated.

[0200] In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 2000 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 1000 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 500 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 200 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 150 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 100 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 50 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmacally acceptable salt thereof, are from about 0.01 to about 25 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 10 mg / kg per body weight. In one embodiment, the daily dosages appropriate for the composition provided herein described herein, or a pharmaceutically acceptable salt thereof, are from about 0.01 to about 5 mg / kg per body weight. In some of these embodiments, the dose relates to mg / kg per body weight of a compound of Formula I or Table 1 (e.g.. Compound II). In some embodiments, the daily dosage or the amount of active in the dosage form are lower or higher than the ranges indicated herein, based on a number of variables in regard to an individual treatment regime. In various embodiments, the daily and unit dosages are altered depending on a number of variables including, but not limited to, the activity of the compound used, the disease or condition to be treated, the mode of administration, the requirements of the individual subject, the severity of tire disease or condition being treated, and the judgment of the practitioner.

[0201] The compounds of the present disclosure is administered to a subject at various dosing amounts per dose or per day. Daily dosage of a compound of Formula I or Table 1 (e.g., Compound II)may be between about 1 mg and 4,000 mg, between about 2,000 to 4.000 mg / day. between about 1 to 2.000 mg / day, between about 1 to 1,000 mg / day, between about 10 to 500 mg / day, between about 20 to 500 mg / day, between about 50 to 300 mg / day, between about 75 to 200 mg / day, or between about 15 to 150 mg / day. For example, from about 0.1 mg / day to 2000 mg / day, from about 0.1 mg / day to 1500 mg / day, from about 0. 1 mg / day to 1000 mg / day, from about 0.1 mg / day to 900 mg / day, from about 0. 1 mg / day to800 mg / day, from about 0.1 mg / day to 700 mg / day, from about 0.1 mg / day to 600 mg / day. from about 0.1 mg / day to 500 mg / day, from about 0.1 mg / day to 400 mg / day, from about 0.1 mg / day to 300 mg / day, from about 0. 1 mg / day to 200 mg / day, from about 0. 1 mg / day to 100 mg / day, from about 0.1 mg / day to 90 mg / day, from about 0.1 mg / day to 80 mg / day, from about 0. 1 mg / day to 70 mg / day, from about 0.1 mg / day to 60 mg / day, from about 0.1 mg / day to 50 mg / day, from about 0.1 mg / day to 40 mg / day. from about 0. 1 mg / day to 30 mg / day, from about 0.1 mg / day to 20 mg / day. from about 0. 1 mg / day to 10 mg / day, from about 0. 1 mg / day to 9 mg / day, from about 0.1 mg / day to 8 mg / day, from about 0. 1 mg / day to 7 mg / day, from about 0.1 mg / day to 6 mg / day, from about 0. 1 mg / day to 5 mg / day, from about 0. 1 mg / day to 4 mg / day, from about 0. 1 mg / day to 3 mg / day, from about 0. 1 mg / day to 2 mg / day, from about 0. 1 mg / day to 1 mg / day, from about 1 mg / day to 2000 mg / day, from about 5 mg / day to 2000 mg / day, from about 10 mg / day to 2000 mg / day, from about 20 mg / day to 2000 mg / day. from about 30 mg / day to 2000 mg / day. from about 40 mg / day to 2000 mg / day, from about 50 mg / day to 2000 mg / day, from about 60 mg / day to 2000 mg / day, from about 70 mg / day to 2000 mg / day, from about 80 mg / day to 2000 mg / day, from about 90 mg / day to 2000 mg / day, from about 100 mg / day to 2000 mg / day, from about 150 mg / day to 2000 mg / day, from about 200 mg / day to 2000 mg / day, from about 250 mg / day to 2000 mg / day, from about 300 mg / day to 2000 mg / day, from about 350 mg / day to 2000 mg / day, from about 400 mg / day to 2000 mg / day, from about 450 mg / day to 2000 mg / day. from about 500 mg / day to 2000 mg / day. from about 550 mg / day to 2000 mg / day, from about 600 mg / day to 2000 mg / day. from about 650 mg / day to 2000 mg / day, from about 700 mg / day to 2000 mg / day, from about 750 mg / day to 2000 mg / day, from about 800 mg / day to 2000 mg / day, from about 850 mg / day to 2000 mg / day, from about 900 mg / day to 2000 mg / day, from about 950 mg / day to 2000 mg / day, from about 1000 mg / day to 2000 mg / day, from about 1500 mg / day to 2000 mg / day, from about 5 mg / day to 1500 mg / day, from about 5 mg / day to 1000 mg / day, from about 5 mg / day to 900 mg / day, from about 10 mg / day to 1000 mg / day. from about 10 mg / day to 900 mg / day, from about 10 mg / day to 800 mg / day, from about 10 mg / day to 700 mg / day, from about 10 mg / day to 600 mg / day, from about 10 mg / day to 500 mg / day, from about 10 mg / day to 400 mg / day, from about 10 mg / day to 300 mg / day, from about 10 mg / day to 200 mg / day, from about 10 mg / day to 100 mg / day, from about 10 mg / day to 90 mg / day, from about 10 mg / day to 80 mg / day, from about 10 mg / day to 70 mg / day, from about 10 mg / day to 60 mg / day, from about 10 mg / day to 50 mg / day, from about 10 mg / day to 40 mg / day, from about 10 mg / day to 30 mg / day. from about 10 mg / day to 20 mg / day, from about 50 mg / day to 1000 mg / day, from about 50 mg / day to 900 mg / day, from about 50 mg / day to 800 mg / day, from about 50 mg / day to 700 mg / day, from about 50 mg / day to 600 mg / day, from about 50 mg / day to 500 mg / day, from about 50 mg / day to 400 mg / day, from about 50 mg / day to 300 mg / day, from about 50 mg / day to 200 mg / day, from about 50 mg / day to 100mg / day, from about 50 mg / day to 90 mg / day, from about 50 mg / day to 80 mg / day, from about 50 mg / day to 70 mg / day, from about 50 mg / day to 60 mg / day.

[0202] In certain embodiments, the dosing amount is equivalent or at least about 0.1 mg / day, about 0.5 mg / day, about 1 mg / day, about 5 mg / day, about 10 mg / day, about 20 mg / day, about 30 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day. about 70 mg / day. about 80 mg / day, about 90 mg / day, about 100 mg / day. about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300 mg / day. about 350 mg / day, about 400 mg / day, about 450 mg / day, about 500 mg / day, about 550 mg / day, about 600 mg / day, about 650 mg / day, about 700 mg / day, about 750 mg / day, about 800 mg / day, about 850 mg / day, about 900 mg / day, about 950 mg / day, about 1000 mg / day, about 1200 mg / day, about 1500 mg / day, or about 2000 mg / day.

[0203] In certain embodiments, dosing amounts of the compounds of the present disclosure per dose or per day is from about 0.1 mg / kg to 200 mg / kg, from about 0. 1 mg / kg to 100 mg / kg. from about 0.1 mg / kg to 90 mg / kg, from about 0. 1 mg / kg to 80 mg / kg, from about 0.1 mg / kg to 70 mg / kg, from about 0.1 mg / kg to 60 mg / kg, from about 0. 1 mg / kg to 50 mg / kg, from about 0.1 mg / kg to 40 mg / kg, from about 0.1 mg / kg to 30 mg / kg, from about 0.1 mg / kg to 20 mg / kg, from about 0.1 mg / kg to 10 mg / kg, from about 0. 1 mg / kg to 9 mg / kg. from about 0.1 mg / kg to 8 mg / kg, from about 0. 1 mg / kg to 7 mg / kg. from about 0. 1 mg / kg to 6 mg / kg. from about 0.1 mg / kg to 5 mg / kg, from about 0.1 mg / kg to 4 mg / kg, from about 0. 1 mg / kg to 3 mg / kg. from about 0.1 mg / kg to 2 mg / kg, from about 0.1 mg / kg to 1 mg / kg, from about 1 mg / kg to 100 mg / kg, from about 1 mg / kg to 200 mg / kg, from about 5 mg / kg to 200 mg / kg, from about 10 mg / kg to 200 mg / kg, from about 20 mg / kg to 200 mg / kg, from about 30 mg / kg to 200 mg / kg, from about 40 mg / kg to 200 mg / kg, from about 50 mg / kg to 200 mg / kg, from about 60 mg / kg to 200 mg / kg, from about 70 mg / kg to 200 mg / kg, from about 80 mg / kg to 200 mg / kg, from about 90 mg / kg to 200 mg / kg, from about 100 mg / kg to 200 mg / kg, from about 150 mg / kg to 200 mg / kg, from about 5 mg / kg to 150 mg / kg, from about 5 mg / kg to 100 mg / kg. from about 5 mg / kg to 90 mg / kg. from about 5 mg / kg to 80 mg / kg, from about 5 mg / kg to 70 mg / kg, from about 5 mg / kg to 60 mg / kg, from about 5 mg / kg to 50 mg / kg, from about 5 mg / kg to 40 mg / kg, from about 5 mg / kg to 30 mg / kg, from about 5 mg / kg to 20 mg / kg, from about 5 mg / kg to 10 mg / kg, from about 10 mg / kg to 100 mg / kg, from about 10 mg / kg to 90 mg / kg, from about 10 mg / kg to 80 mg / kg, from about 10 mg / kg to 70 mg / kg. from about 10 mg / kg to 60 mg / kg, from about 10 mg / kg to 50 mg / kg, from about 10 mg / kg to 40 mg / kg. from about 10 mg / kg to 30 mg / kg, from about 10 mg / kg to 20 mg / kg, from about 10 mg / kg to 15 mg / kg.

[0204] In certain embodiments, the dosing amount of the compounds per dose or per day of the present disclosure is equivalent to or at least about 0. 1 mg / kg, 0.2 mg / kg, 0.3 mg / kg, 0.4 mg / kg, 0.5 mg / kg, 0.6 mg / kg, 0.7 mg / kg, 0.8 mg / kg, 0.9 mg / kg, 1 mg / kg, 2 mg / kg, 3 mg / kg, 4 mg / kg, 5 mg / kg, 6 mg / kg, 7 mg / kg, 8 mg / kg, 9 mg / kg, 10 mg / kg, 15 mg / kg, 20mg / kg, 25 mg / kg, 30 mg / kg, 35 mg / kg. 40mg / kg,45mg / kg, 50mg / kg, 55mg / kg, 60 mg / kg, 65mg / kg, 70mg / kg, 75mg / kg, 80 mg / kg, 85mg / kg, 90mg / kg, 95mg / kg, lOOmg / kg, 150mg / kg, 180mg / kg, or 200 mg / kg.

[0205] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of tire composition provided herein, including further embodiments in which (i) the compound is administered once a day; (ii) the composition provided herein is administered to the patient twice in the one day. or (iii) the composition provided herein is administered to the patient multiple times over the span of one day.

[0206] In any of the aforementioned aspects are further embodiments comprising multiple administrations of the effective amount of the composition or compounds provided herein, including further embodiments in which (i) the composition or compounds provided herein is administered continuously or intermittently as in a single dose; (ii) the time between multiple administrations is every- 6 hours: (iii) the composition or compounds provided herein is administered to the patient every- 8 hours; (iv) the composition or compounds provided herein is administered to the patient every 12 hours; (v) the composition or compounds provided herein is administered to the patient every 24 hours. In further or alternative embodiments, the method comprises a drug holiday, wherein the administration of the composition provided herein is temporarily suspended or the dose of tire composition provided herein being administered is temporarily reduced; at the end of the drug holiday, dosing of the composition provided herein is resumed. In one embodiment, the length of the drug holiday varies from about 2 days to 1 year.

[0207] In certain instances, it is appropriate to administer composition or compounds provided herein described herein, in combination with one or more other tirerapeutic agents.

[0208] In one embodiment, the therapeutic effectiveness of one of the composition provided herein described herein is enhanced by administration of an adjuvant (z.e., by itself the adjuvant has minimal therapeutic benefit, but in combination yvith another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, in some embodiments, the benefit experienced by a patient is increased by administering one of the composition provided herein described herein yvith another agent (yvhich also includes a therapeutic regimen) that also has tirerapeutic benefit.

[0209] In one specific embodiment, a composition or compounds provided herein described herein is coadministered with a second therapeutic agent, wherein the composition or compounds provided herein and the second therapeutic agent modulate different aspects of the disease, disorder or condition being treated, thereby providing a greater overall benefit than administration of either therapeutic agent alone. In certain embodiments, the second therapeutic agent includes, but are not limited to non-steroidal antiinflammatory drugs (NSAIDs) or vitamin B6.

[0210] In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient is simply be additive of the two therapeutic agents or the patient experiences a synergistic benefit.

[0211] In certain embodiments, different therapeutically-effective dosages of the compounds in the composition provided herein disclosed herein will be utilized in formulating pharmaceutical composition and / or in treatment regimens when the composition provided herein disclosed herein are administered in combination with one or more additional agent, such as an additional therapeutically effective drug, an adjuvant or the like. Therapeutically-effective dosages of drags and other agents for use in combination treatment regimens is optionally determined by means similar to those set forth hereinabove for the actives themselves. Furthermore, the methods of prevention / treatment described herein encompasses the use of metronomic dosing, i.e., providing more frequent, lower doses in order to minimize toxic side effects. In some embodiments, a combination treatment regimen encompasses treatment regimens in which administration of a composition provided herein described herein, or a pharmaceutically acceptable salt thereof, is initiated prior to, during, or after treatment with a second agent described herein, and continues until any time during treatment with the second agent or after termination of treatment with the second agent. It also includes treatments in which a composition provided herein described herein and the second agent being used in combination are administered simultaneously or at different times and / or at decreasing or increasing intervals during the treatment period. Combination treatment further includes periodic treatments that start and stop at various times to assist with the clinical management of the patient.

[0212] It is understood that the dosage regimen to treat, prevent, or ameliorate the disease(s) for which relief is sought, is modified in accordance with a variety of factors (e.g. the disease or disorder from about which the subject suffers; the age, weight, sex, diet, and medical condition of the subject). Thus, in some instances, the dosage regimen actually employed varies and. in some embodiments, deviates from about the dosage regimens set forth herein.

[0213] For combination therapies described herein, dosages of the co-administered composition provided herein vary depending on the type of co-drug employed, on the specific drag employed, on the disease or condition being treated and so forth. In additional embodiments, when co-administered with one or more other therapeutic agents, the composition provided herein described herein is administered either simultaneously with the one or more other therapeutic agents, or sequentially.

[0214] In combination therapies, the multiple therapeutic agents (one of which is the composition provided herein described herein) are administered in any order or even simultaneously. If administration is simultaneous, the multiple therapeutic agents are, by way of example only, provided in a single, unified form, or in multiple forms (e.g., as a single pill or as two separate pills).

[0215] The composition described herein, or a pharmaceutically acceptable salt thereof, as well as combination therapies, are administered before, during or after the occurrence of a disease or condition, and the timing of administering the formulation containing a compound varies. Tirus, in one embodiment, the composition provided herein described herein is used as a prophylactic and are administered continuously to subjects with a propensity to develop conditions or diseases in order to prevent the occurrence of the disease or condition. In another embodiment, the composition provided herein is administered to a subject during or as soon as possible after the onset of the symptoms. In specific embodiments, a composition provided herein described herein is administered as soon as is practicable after the onset of a disease or condition is detected or suspected, and for a length of time necessary for the treatment of the disease. In some embodiments, the length required for treatment varies, and the treatment length is adjusted to suit the specific needs of each subject. For example, in specific embodiments, a formulation containing the compound is administered for at least 2 weeks, about 1 month to about 5 years.

[0216] In certain embodiments, the treatment with the compound or composition provided herein improves muscle strength, as measured using the endpoint methods illustrated below.

[0217] In certain embodiments, the treatment with the compound or composition provided herein reduces pain, as measured by e.g. QoL, PODCI or BPI-SF questionnaire. In certain embodiments, the pain includes muscle pain and / or joint pain.

[0218] In certain embodiments, the pain scores, as measured by QoL, PODCI or BPI-SF questionnaire has been reduced by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% or more.

[0219] To test the treatment effect, multiple endpoints may be used. Some such endpoints used in HPP treatment include, but are not limited to. the Rickets Severity Scale (RSS) score, the osteoid thickness, the Radiographic Global Impression of Change (RGI-C) scale, Bruininks-Oseretsky Test of Motor Proficiency 2nd Edition (BOT-2), the Bayley Scales of Infant and Toddler Development, 3rd Edition (BSI D-III), the Childhood Health Assessment Questionnaire (CHAQ), the Pediatric Outcomes Data Collection Instrument test (PODCI), the Peabody Developmental Motor Scales, 3rd Edition (PDMS-3), six-minute walk test (6MWT), tire Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), the 12- point performance-oriented mobility assessment (POMA-G), a modified performance-oriented mobility assessment (mPOMA-G, such as the one illustrated in Phillips et al. 2015 Bone Abstracts 4.P136), the Timed Up-and-Go (TUG), the Baseline in Lower Extremity Functional Scale (LEFS) Score, the 30- second Sit to Stand (STS) Test Score, the Hip extensor and abductor muscle strength measurement using handheld dynamometer, the Bone mineral density Z-score using Dual-energy X-ray absorptiometry, andother methods or tests known in the art. Both naive patients and patients having been administered with other alkaline phosphatase therapy may be treated with the compounds or composition provided herein.

[0220] Tire methods provided herein improves the score as measured with at least one of the above functional efficacy endpoint. For example, after administering of the compounds or compositions provided herein.-the average BOT-2 strength score has been increased from about 10 or less (e.g. less than about 7) to about 10 or more, such as about 12-16, about 10-20, or 18 or greater;—the average BOT-2 running speed and agility score has been increased from about 5 or less to about 5 or more, such as about 9-13, or about 5-20;—the average CHAQ index score has been decreased from about 0.8 or more to about 0.5 or less, such as 0 to 0.5;-the average PODCI score has increased from about 40 or less to about 40 or more, such as about 40-50;—the average mPOMA-G score has increased to about 7.5, about 8, about 8.5, about 9, about 9.5, about 10, about 10.5, about 11, about 11.5, or about 12, or increased by at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% or more;-the average Muscle Strength Grade has been increased by about 1 or more from about the average Muscle Strength Grade of less than about 5;—the average handheld dynamometer (HHD) value has been increased from about less than about 50-80% of a predicted HHD value to about 50-80% or more of a predicted HHD value;—the average 6MWT has been increased by at least about 20 meters, about 30 meters, about 35 meters, about 40 meters, about 45 meters, about 50 meters, about 55 meters, about 60 meters, about 65 meters, about 70 meters, about 75 meters, about 80 meters, about 85 meters, about 90 meters, about 95 meters, or about 100 meters or more (e.g. 500 meters), or increased by at least about 10%. at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60% or more;—the average LEFS score has been increased by about 9 or more;—the average osteoid thickness has been decreased from about 12 pm or more to about 3 pm to 12 pm;-the average TUG score has been decreased from about 13.5 seconds or longer to about 13.5 seconds or shorter;—the average RSS score has been increased from about;‘-3”-“0” to “0”-"‘+3”;— the average STS score has been increased from about 10 or less to 10 or more sit-to-stand cycles in 30 seconds;-the average BSID-III score has been increased from about less than 2 to 5 or more (e.g. 6 or 7); or— the average BMD Z-score has been increased from about -2.0 or lower to -2.0 or higher.

[0221] In certain embodiments, tire course of the treatment or prevention lasts at least one day, two days, three days, four days, five days, six days, one week, two weeks, three weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, ten months, eleven months, one year, two years, at least three years, at least four years, or longer (e.g., at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years, or more than ten years, such as for the lifetime of the subject). In certain embodiments, the treatment or prevention lasts about 1 to 10 years, about 2 to 10 years, about 3 to 10 years, about 4 to 10 years, about 5 to 10 years, about 6 to 10 years, about 7 to 10 years, about 1 to 5 years, about 2 to 5 years, about 3 to 5 years, or about 2 to 6 years.

[0222] In certain embodiments, the improvements resulting from about administration of the compounds or compositions provided herein are sustained during the course of treatment or prevention.

[0223] In certain embodiments, provided is a method of treating or preventing hypophosphatasia in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, disclosed in W02022091048A1, US20220135598A1, US20240352046A1, WO2021226136A1, US20230190927A1. W02023035001A1, US20240374724A 1 , W02023077083 A 1 , US20230002387A 1 , W02023220402A 1 , WO2023109909A 1 , WO2023143520A1, WO2024074128A1, US20220411420A1, WO2023242631A1, WO2019046778A1, US20200291024A1, US20230183239A1, WO2019177971A1, US20190282703A1, W02019191504A1, US20210023234A1, W02021061803A1, W02020140001A1, US20220056052A1, W02020210649A1, US20220362266A1, WO2022197734A1, WO2022212488A1, WO2024148272A1, WO2021133915A1, WO2024149239A1. WO2024199444A1, CN 115536696A, WO2023197987, WO2024028727A1.WO2024127343 A 1 , US20230103498A 1 , WO2019051269A 1 , US20210369747A 1 , US20230103498A 1 , US20230277570A1, US20220289775A1, US20190031655A1, WO2019023635A1, US20200039979A1, W02020028724A1, US20200299258A1, W02020190912A1, WO2021158829A1, US20210253556A1, US20230183212A1, WO2022119928A1, WO2021225407A1, US20230159469A1, WO2022146022A1, US20240140944A1, WO2022164249A1, US20240116882A1, US20230270767A1. WO2021225954A1, US20220033512A1. W02022056068A1. WO2021231726A1, US20230183188A1. WO2023086638A1, W02023225001A1, WO2021225969A1, WO2021257614A1, US20230036933A1, US20240376113A1, US2025 / 0101019A1, W02025 / 007955A1, WO2025 / 026377A1, WO2025 / 026383A1, or Gangar, et al., Bioorganic Chemistry, Volume 119, February 2022, 105549 (e.g., compound 43); a compound, or a pharmaceutically acceptable salt thereof, shown in Table A; orISM5939, SR-8541A, MV-626, TXN10128, ZX-8177, STF-1623, or RBS2418.

[0224] In certain embodiments, the hypophosphatasia is selected from the group consisting of late-onset hypophosphatasia, prenatal hypophosphatasia, perinatal hypophosphatasia, infantile hypophosphatasia, childhood hypophosphatasia, adult hypophosphatasia, odontohypophosphatasia, and hypophosphatasia that has dental involvement and / or premature tooth loss.

[0225] In certain embodiments, provided is a method of treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of an inhibitor of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1). wherein the subject is characterized as having at least one symptom of HPP, and wherein the subject is a treatment naive subject, an enzyme replacement therapy (EZRT) intolerant or resistant subject, previously treated with EZRT, or refractory to, or has relapsed from the EZRT, and wherein the subject is: an adult with childhood-onset HPP; an adult with adult-onset HPP; a juvenile with childhood-onset HPP; or an infant with infantile HPP.

[0226] In certain embodiments, provided is a method of treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of an inhibitor of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1) (e g., a compound of Formula I or Table 1); a compound, or a pharmaceutically acceptable salt thereof, disclosed in W02022091048A1, US20220135598A1, US20240352046A 1, WO2021226136A1, US20230190927A1, W02023035001 Al, US20240374724A1, W02023077083A1, US20230002387A1, W02023220402A1, W02023109909A1, WO2023143520A1, WO2024074128A1, US20220411420A1, WO2023242631A1, WO2019046778A1, US20200291024A1, US20230183239A1, WO2019177971A1, US20190282703A1, W02019191504A1, US20210023234A1, W02021061803A1, W02020140001A1, US20220056052A1. W02020210649A1, US20220362266A1. WO2022197734A1, WO2022212488A1, WO2024148272A1. WO2021133915A1, WO2024149239A 1 , WO2024199444A 1 , CN1 15536696A, WO2023197987, WO2024028727A 1 , WO2024127343 Al, US20230103498A1, WO2019051269A1, US20210369747A1, US20230103498A1, US20230277570A1, US20220289775A1, US20190031655A1, WO2019023635A1, US20200039979A1, W02020028724A1, US20200299258A1, W02020190912A1, WO2021158829A1, US20210253556A1,US20230183212A1, WO2022119928A1, WO2021225407A1, US20230159469A1, WO2022146022A1, US20240140944A1, WO2022164249A1, US20240116882A1, US20230270767A1, WO2021225954A1, US20220033512A1, W02022056068A1, WO2021231726A1, US20230183188A1, WO2023086638A1, W02023225001A1, WO2021225969A1, WO2021257614A1. US20230036933A1, US20240376113 A 1 , US2025 / 0101019A1, W02025 / 007955A1, WO2025 / 026377A1, WO2025 / 026383A1, or Gangar, et al., Bioorganic Chemistry, Volume 119. February 2022. 105549 (e.g.. compound 43): a compound, or a pharmaceutically acceptable salt thereof, shown in Table A: orISM5939, SR-8541A, MV-626, TXN10128, ZX-8177, STF-1623, or RBS2418; wherein the subject is characterized as having at least one symptom of HPP, and wherein the subject is a treatment naive subject, an enzyme replacement therapy (EZRT) intolerant or resistant subject, previously treated with EZRT, or refractory to, or has relapsed from the EZRT, and wherein the subject is: an adult with childhood-onset HPP; an adult with adult-onset HPP; a juvenile with childhood-onset HPP; or an infant with infantile HPP.

[0227] In certain embodiments, the at least one symptom of HPP comprises at least one of pathogenic or likely pathogenic ALPL gene mutation, elevated blood and / or urine levels of natural substrates, poorly healing fractures, chondrocalcinosis, nephrocalcinosis, rickets, early atraumatic loss of teeth, premature loss of deciduous teeth, short stature or linear growth failure over time, delayed motor milestones, craniosynostosis, B6 responsive seizures, incomplete bone mineralization, elevated blood and / or urine levels of inorganic pyrophosphate (PPi), elevated blood levels of phosphoethanolamine (PEA), elevated urine levels of PEA, elevated blood levels of pyridoxal 5 ’-phosphate (PLP), elevated urine levels of PLP, hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture (such as atypical femoral fractures or recurrent metatarsal fractures), HPP-related seizure, inadequate weight gain, and calcium pyrophosphate dihydrate crystal deposition.

[0228] In certain embodiments, administering the compound, or a pharmaceutically acceptable salt thereof, reduces urine levels of inorganic pyrophosphate (PPi) in the subject.

[0229] In certain embodiments, administering the compound, or a pharmaceutically acceptable salt thereof, reduces plasma levels of inorganic pyrophosphate (PPi) in the subject.

[0230] In certain embodiments, the method comprises improving in the subject at least one of a Radiographic Global Impression of Change (RGI-C) score, Rickets Severity Scale (RSS) score, or osteoid thickness.

[0231] In certain embodiments, the method comprises improving in the subject at least one of the functional efficacy endpoints selected from the group consisting of Peabody Developmental Motor Scales, Third Edition (PDMS-3) Score, Childhood Health Assessment Questionnaire (CHAQ) disability index score, Pediatric Outcomes Data Collection Instrument (PODCI), Percent 6-minute walk test (6MWT), Timed Up-and-Go (TUG), Lower Extremity Functional Scale (LEFS) Score, Muscle Strength Grade, 30-second Sit to Stand (STS) Test Score, handheld dynamometer (HHD), Bone mineral density Z- score using Dual -energy X-ray absorptiometry. Brief Pain Inventory' - Short Form (BPI-SF) questionnaire, Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Bruininks- Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), and modified perfonnance-oriented mobility assessment-gait (MPOMA-G).

[0232] In certain embodiments, the method provides improved muscle strength or reduced pain.

[0233] In certain embodiments, the pain is from muscle pain and / or joint pain.

[0234] In certain embodiments, the treatment or prevention lasts at least one year, at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years or longer.EXAMPLESSeparation of isomers of N-(2-(7-chloro-5-methylpyrrolo[2,l-f][l,2,4]triazin-4-yl)-2- azaspiro[3.3]heptan-6-yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamide (Compounds VIII and IX)

[0235] N-(2-(7-chloro-5-methylpyrrolo[2,l-f][l,2,4]triazin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-N-(3,3,3- trifluoro-2-hydroxypropyl)sulfamide was prepared according to the procedure outlined in US 12,325,720. The enantiomers of N-(2-(7-chloro-5-methylpyrrolo[2,I-fj[I,2,4]triazin-4-yl)-2-azaspiro[3.3]heptan-6- yl)-N-(3,3,3-trifluoro-2-hydroxypropyl)sulfamide (30 mg) were separated by chiral chromatography toafford Compound VIII as the first eluting isomer and Compound IX as the second eluting isomer. Separation conditions: Instrument: Waters Acquity UPLC-MS SQD 3100; 5 Column: Acquity BEH Shield RP 18, 50 * 2.1 mm, 1.7pm; Eluent A: 0.05% Trifluoroacetic acid in Water, Eluent B: Acetonitrile: Gradient: 10 %B to 90 %B in 4.5 min, hold for 3 min, 90% B to 10% B in 0.5 min (Run Time: 10.0 min); Flow rate: 0.35 mL / min; Temperature: 25°C, PDA scan: 210 nm - 400 nm.Example 1. Impact of compounds on PPi levels in WT animals after a single dose

[0236] The effect of an exemplary compound of the present disclosure on PPi levels in wild-type animals was examined. Compound II was orally dosed to 6-8-week-old C57BL / 6J mice (n=5) and 6-8-week old female SD rats (n=5) at lOOmg / kg, QD as single dose. Plasma samples were taken at pre-dose and 1, 8 and 24 hours post-dose from rats, and at 8 and 24 hours post-last dose from mice in heparin SST tubes and spun down (7000 rpm x 10 min) immediately. For PPi analysis, the platelet removal step was perfonned by spinning down the plasma with a Spin-X column (0.22 pM. Costar 8160) immediately (7000 rpm x 2 min) and the eluted plasma was aliquoted / frozen down on dry ice immediately. Prior to PPi analysis, plasma samples were de-proteinated with a 10 kD cutoff column (Amicon #UFC501024) (4 °C). PPi from fdtered plasma was first converted to ATP by ATP sulfurylase (R&D# 7175-AS-020) in the presence of adenosine phosphosulfate (APS; Sigma# A5508). Reactions were incubated at 37°C for 30 minutes followed by 10 minutes at 90°C to deactivate ATP sulfurylase. The resulting ATP was then quantified with Bactiter Gio detection reagent (Promega G8230; Madison, Wl, USA). To account for endogenous ATP present in the plasma, a blank reaction was run for each sample with heat-inactivated ATP sulfurylase. The luminescent signals from this reaction were subtracted from the total luminescent signals to calculate the plasma PPi levels..

[0237] Compound II is able to reduce the PPi levels in Mouse and Rat in a time -dependent manner after a single dose, as shown in FIG. 1A and FIG. IB.Example 2 . Impact of compounds on PPi levels in Beagle dogs after a single dose

[0238] The effect of an exemplary compound of the present disclosure on PPi levels in wild-type Beagle dogs was examined. Compound II was orally dosed to 2 Beagle Dogs (n=2) at 50mg / kg, QD as single dose. Plasma samples were taken at pre-dose, 0.5, 1, 2, 4, 8 and 24 hours post-dose from Cephalic vein in heparin SST tubes and spun down (7000 rpm x 10 min) immediately. For PPi analysis, the platelet removal step was perfonned by spinning down the plasma with a Spin-X column (0.22 pM. Costar 8160) immediately (7000 rpm x 2 min) and the eluted plasma was aliquoted / frozen down on dry ice immediately. Prior to PPi analysis, plasma samples were de-proteinated with a 10 kD cutoff column (Amicon #UFC501024) (4 °C). PPi from filtered plasma was first converted to ATP by ATP sulfury lase (R&D# 7175-AS-020) in the presence of adenosine phosphosulfate (APS; Sigma# A5508). Reactions were incubated at 37°C for 30 minutes followed by 10 minutes at 90°C to deactivate ATP sulfurylase.The resulting ATP was then quantified with Bactiter Gio detection reagent (Promega G8230; Madison, WI, USA). To account for endogenous ATP present in the plasma, a blank reaction was run for each sample with heat-inactivated ATP sulfurylase. The luminescent signals from this reaction were subtracted from the total luminescent signals to calculate the plasma PPi levels.

[0239] Compound II is able to reduce the plasma PPi levels in Beagle dogs after a single dose, as shown in FIG. 1C.Example 3 . Impact of compounds on urine and plasma PPi levels in WT animals

[0240] The effect of an exemplary compound of the present disclosure on plasma and urine PPi levels in wild-type animals was examined. Compound II was orally dosed to 6-8-week old C57BL / 6J, female mice (n=5) at 30 and 100 mg / kg, in a single dose. AA (MCE# HY-108786) was dosed at 8.2mg / kg, SC as single dose. Plasma samples were taken at 8 hours post-dose from mice in heparin SST tubes and spun down (7000 rpm x 10 min) immediately and, the platelet removal step was performed by spinning down the plasma with a Spin-X column (0.22 pM, Costar 8160) immediately (7000 rpm x 2 min) and the eluted plasma was aliquoted / frozen down on dry ice immediately. Prior to PPi analysis, plasma samples were de-proteinated with a 10 kD cutoff column (Amicon #UFC501024) (4 °C). Urine samples were collected in metabolic cage at 8 hours post-dose from about mice. Urine samples were spun down with 3K filtration (Pall# OD003C35). PPi from filtered plasma and urine was first converted to ATP by ATP sulfurylase (R&D# 7175-AS-020) in the presence of adenosine phosphosulfate (APS: Sigma# A5508). Reactions were incubated at 37°C for 30 minutes followed by 10 minutes at 90°C to deactivate ATP sulfurylase. The resulting ATP was then quantified with Bactiter Gio detection reagent (Promega G8230; Madison, WI, USA). To account for endogenous ATP present in the urine, a blank reaction was run for each sample with heat-inactivated ATP sulfurylase. The luminescent signals from about this reaction were subtracted from about the total luminescent signals to calculate the urine PPi levels.

[0241] Compound II is able to reduce the plasma PPi levels in Mouse and urine PPi in a dose-dependent manner after a single dose, as shown in FIG. 2A and FIG. 2B as compared to asfotase alfa (AA).Example 4 . Impact of compounds on Urine PPi levels in WT animals

[0242] Compounds shown in Table 1 were orally dosed to 6-8-week old C57BL / 6J, Female mice (n=3) at 30 and lOOmg / kg. in a single dose. The mice were allowed to defecate in a clean petri dish, and then the urine was collected in a tube at 8 hours post-dose. For PPi analysis urine was first converted to ATP by ATP sulfurylase (R&D# 7175-AS-020) in the presence of adenosine phosphosulfate (APS: Sigma# A5508).

[0243] Reactions were incubated at 37°C for 30 minutes followed by 10 minutes at 90°C to deactivate ATP sulfurylase. The resulting ATP was then quantified with Bactiter Gio detection reagent (Promega G8230; Madison, WI, USA). To account for endogenous ATP present in the urine, a blank reaction wasrun for each sample with heat-inactivated ATP sulfurylase. The luminescent signals from about this reaction were subtracted from about the total luminescent signals to calculate the urine PPi levels.

[0244] As shown in FIG. 3, Compounds shown in Table 1 were able to reduce the PPi levels in Mouse urine in a dose-dependent manner after a single dose as compared to vehicle.Example 5: Impact of compounds on Plasma PPi levels in WT animals

[0245] The effect of an exemplary compounds of the present disclosure on PPi levels in wild-type animals was examined Compounds were orally dosed to 6-8-week old female SD rats (n=3) at 30 mg / kg and lOOmg / kg, in a single dose. Plasma samples were taken at 8 hours post-dose from mice in heparin SST tubes and spun down (7000 rpm x 10 min) immediately. For PPi analysis, the platelet removal step was performed by spinning down the plasma with a 0.22um filter (SLGPR33RB) immediately (7000 rpm x 2 min) and the eluted plasma was aliquoted / frozen down on dry ice immediately. Prior to PPi analysis, plasma samples were de-proteinated with a 10 kD cutoff column (Amicon #UFC501024) (4 °C). PPi from filtered plasma was first converted to ATP by ATP sulfurylase (R&D# 7175-AS-020) in the presence of adenosine phosphosulfate (APS; Sigma# A5508). Reactions were incubated at 37°C for 30 minutes followed by 10 minutes at 90°C to deactivate ATP sulfurylase. The resulting ATP was then quantified with Bactiter Gio detection reagent (Promega G8230; Madison, WI, USA). To account for endogenous ATP present in the plasma, a blank reaction was run for each sample with heat-inactivated ATP sulfurylase. The luminescent signals from this reaction were subtracted from the total luminescent signals to calculate the plasma PPi levels.

[0246] As shown in FIG. 4 and Table 3, Compounds shown in Table 1 were able to reduce the PPi levels in Mouse plasma in a dose-dependent manner after a single dose as compared to vehicle.Table 3: Summary of Results:* * *

[0247] The present disclosure is not to be limited in scope by the specific embodiments described which are intended as single illustrations of individual aspects of the disclosure, and any compositions or methods which are functionally equivalent are within the scope of this disclosure. It will be apparent to those skilled in the art that various modifications and variations can be made in the methods and compositions of the present disclosure without departing from about the spirit or scope of the disclosure. Tirus, it is intended that the present disclosure cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.

[0248] All publications and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

Claims

1. CLAIMS1. A method of treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of an inhibitor of ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), wherein the subject is characterized as having at least one symptom of HPP, and wherein the subject is a treatment naive subject, an enzy e replacement therapy (EZRT) intolerant or resistant subject, previously treated with EZRT, or refractory to, or has relapsed from the EZRT, and wherein the subject is: an adult with childhood-onset HPP; an adult with adult-onset HPP; a juvenile with childhood-onset HPP; or an infant with infantile HPP.

2. A method of treating or preventing one or more symptoms of hypophosphatasia (HPP) in a subject in need thereof, the method comprising orally administering to the subject a therapeutically effective amount of a compound having the structure:or a pharmaceutically acceptable salt thereof, wherein:Ring C is 5- to 6-membered heteroaryl;Ring D is C.,-ar l or 5- to 6-membered heteroaryl, wherein Ring D is fused to Ring C;A is hydrogen, Ci-Ce alkyl, or Cs-aryl, each of which is optionally substituted with halogen;G is a bond, -CH2-, or -CH2-CH2-;Raand Rbare independently hydrogen or Ci-Ce alkyl; or Raand Rbare taken together with the atoms to which they are attached to form a C3-Ce cycloalkyl ring; or any one of Raand Rb. and A are taken together along with the atoms to which they are attached to form a C4-C6 cycloalkyl ring;L is a bond, linear or branched Ci-Ce alkylene, or linear or branched C2-C6 alkenylene; t is 0 or 1; provided that when t is 0. then L is linear or branched C2-C6 alkenylene;Z is -NRCS(O)2NH2, -NRCS(O)2CH3, -SO2NH2, -NRCC(O)CH3, -C(O)OH, -CONH2, -NRCC0NH2, -CONH(OH), -B(OH)2, -P(O)(OH)2, -SO2OH. -NRCS(O)2CF3. -NRCS(O)2NHCH3, or -NRcCH2C6-aiyl-S(O)2NH2. each R1and R2is independently oxo, Ci-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl. C3-Ce cycloalkyl, adamantyl, 3- to 6-membered heterocyclyl, C,-aryl. 5- to 6-membered heteroaryl, -CN, halogen, Ci-C6alkoxy, Ci-C6haloalkoxy, -OR10, -SR10, -S(O)2R10, -S(O)2NRnR12, -NR10S(O)2Rn, -NRnR12, -C(O)R10, -NR10C(O)Rn, -NR10C(O)NRnR12, -C(O)OR10, -C(O)ONRnR12, or -C(O)NRnR12, wherein each is independently optionally substituted by R9; or two R2are taken together with the atoms to which they are attached to form a G-C, cycloalkyl, 5- to 6-membered heterocyclyl, Ce-aryl, or 5- to 6-membered heteroaryl, wherein each is independently optionally substituted by R9: each R9is independently selected from about tire group consisting of oxo, C2-C6 alkenyl, C2-C6 alkynyl, C3-Ce cycloalkyl. 3- to 6-membered heterocyclyl. Ce-aryl, 5- to 6-membered heteroaryl, -CN, halogen. Ci-C6alkoxy, Ci-C6haloalkoxy, Ci-C6haloalkyl. -OR13, -SR13. -S(O)2R13, -S(O)2NR14R15, - NR13S(O)2R14, -NR14R15, -C(O)R13, -NR13C(O)R14, -NR13C(O)NR14R15, -C(O)OR13, -C(O)ONR14R15, - C(O)NR14R15, and Ci-Ce alkyl optionally substituted by oxo, -OH, or halogen; each Rcis independently hydrogen, Ci-Ce alkyl, C3-Ce cycloalkyl, -(Ci-Ce alkylene)C3-C6 cycloalkyl, 3- to 6-membered heterocyclyl, -(Ci-Ce alkylene)3- to 6-membered heterocyclyl, -(Ci-Cg alkylcnc)C6-aryl, 5- to 6-mcmbcrcd hctcroaryl, -(Ci-Ce alkylcnc)5- to 6-mcmbcrcd hctcroaryl, Ci-Ce haloalkyl, -(Ci-C6alkylene)OR13, -(Ci-C6alkylene)SR13, -(Ci-C6alkylene) S(O)2R13, -(Ci-C6alkylene)S(O)2NR14R15, -(Ci-C6alkylene)NR13S(O)2R14, -(Ci-C6alkylene)NR14R15, -(Ci-C6alkylene)C(O)R13, -(Ci-C6alkylene)NR13C(O)R14, -(Ci-C6alkylene)NR13C(O)NR14R15, -(Ci-C6alkylene)C(O)OR13, -(Ci-Ce alkylene) C(O)ONR14R15, or -(Ci-Ce alkylene)-C(O)NR14R15, wherein each is independently optionally substituted with Rd;each Rdis independently selected from about the group consisting of halogen, -OH, oxo, -CN, Ci- Cg haloalkyl, Ci-Cg alkoxy, Ci-Cg haloalkoxy, -COOH, and Ci-Cg alkyl optionally substituted with -OH, halogen, CN, or oxo; each R10, R11, and R12is independently hydrogen, Ci-Cg alkyl, Cj-Ce alkenyl, C2-C6 alkynyl, Cs-Ce cycloalkyl, -(Ci-Cg alkylene) C3-Cg cycloalkyl, 3- to 6-membered heterocyclyl, or -(Ci-Cg alkylene)3- to 6-membered heterocyclyl, wherein each of R10, R11and R12is independently optionally substituted by oxo, C2-C6 alkenyl, C2-C6 alkynyl, -CN, halogen, Ci-C, alkoxy. or Ci-C alkyl optionally substituted by oxo, -OH, or halogen; or R11and R12are taken together with the atom(s) to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo. -OH, halogen, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; each R13, R1andR15is independently hydrogen. Ci-Cg alkyl, C2-C6 alkenyl. C2-C6 alkynyl, Ci-Cg haloalkyl, C3-Cg cycloalkyl, or 3- to 6-membered heterocyclyl, wherein each of R10, R11, and R12is independently optionally substituted by oxo, -OH, C2-C6 alkenyl, C2-Cg alkynyl, -CN, halogen, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; or R14and R15are taken together with the atoms to which they are attached to form a 3-6 membered heterocyclyl optionally substituted by oxo, -OH, halogen, or Ci-Cg alkyl optionally substituted by oxo, -OH, or halogen; m is 0, 1 or 2; and n is 0, 1, 2, 3 or 4; provided that when Z is -NRcS(O)3CH3, -CONH2or -C(O)OH, G is a bond, and t is 1, then L is not a bond; wherein the subject is characterized as having at least one symptom of HPP, and wherein the subject is a treatment naive subject, an enzyme replacement therapy (EZRT) intolerant or resistant subject, previously treated with EZRT, or refractory to, or has relapsed from the EZRT, and wherein the subject is: an adult with childhood-onset HPP; an adult with adult-onset HPP; a juvenile with childhood-onset HPP; or an infant with infantile HPP.

3. The method of claim 2, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.The method of claim 2, wherein the compound is Compound II:or a pharmaceutically acceptable salt thereof.The method of claim 2, wherein the compound is Compound III:or a pharmaceutically acceptable salt thereof.

6. Tire method of claim 2, wherein the compound is Compound VI:or a pharmaceutically acceptable salt thereof.

7. The method of claim 2, wherein the compound is Compound V :or a pharmaceutically acceptable salt thereof.

8. The method of claim 2, wherein the compound is Compound VI:or a pharmaceutically acceptable salt thereof.

9. Tire method of claim 2, wherein the compound is Compound VII:or a pharmaceutically acceptable salt thereof.

10. The method of claim 2, wherein the compound is Compound VIII:or a pharmaceutically acceptable salt thereof.

11. The method of claim 2, wherein the compound is Compound IX:or a pharmaceutically acceptable salt thereof.

12. Tire method of claim 2, wherein the compound is Compound X:or a pharmaceutically acceptable salt thereof.

13. The method of claim 2, wherein the compound is Compound XI:or a pharmaceutically acceptable salt thereof.

14. Tire method of claim 2, wherein the compound is Compound XII:or a pharmaceutically acceptable salt thereof.

15. The method of claim 2, wherein the compound is Compound XIII:or a pharmaceutically acceptable salt thereof.

16. The method of any one of claims 1-15, wherein the at least one symptom of HPP comprises at least one of pathogenic or likely pathogenic ALPL gene mutation, elevated blood and / or urine levels of natural substrates, poorly healing fractures, chondrocalcinosis, nephrocalcinosis, rickets, early atraumatic loss of teeth, premature loss of deciduous teeth, short stature or linear growth failure over time, delayed motor milestones, craniosynostosis, B6 responsive seizures, incomplete bone mineralization, elevated blood and / or urine levels of inorganic pyrophosphate (PP0, elevated blood levels of phosphoethanolamine(PEA), elevated urine levels of PEA, elevated blood levels of pyridoxal 5 ’-phosphate (PLP), elevated urine levels of PLP, hypomineralization, rachitic ribs, hypercalciuria, short stature, skeletal deformity, waddling gait, bone pain, bone fracture (such as atypical femoral fractures or recurrent metatarsal fractures), HPP-related seizure, inadequate weight gain, and calcium pyrophosphate dihydrate crystal deposition.

17. The method of any one of claims 1-16, wherein the administering comprises a dose of about 10 mg / day - 300 mg / day.

18. The method of any one of claims 1-16, wherein the administering comprises a dose of at least about 10 mg / day .

19. The method of any one of claims 1-18, wherein the administering comprises one dose per day, two doses per day, three doses per day, or one dose per two days.

20. The method of any one of claims 1-19, wherein administering the Fonnula I or Table 1, or a pharmaceutically acceptable salt thereof, reduces urine levels of inorganic pyrophosphate (PPi) in the subject.

21. The method of any one of claims 1-20, wherein administering the Fonnula I or Table 1. or a pharmaceutically acceptable salt thereof, reduces plasma levels of inorganic pyrophosphate (PPi) in the subject.

22. The method of any one of claims 1-21, wherein the method comprises improving in the subject at least one of a Radiographic Global Impression of Change (RGI-C) score, Rickets Severity Scale (RSS) score, or osteoid thickness.

23. The method of any one of claims 1-22, wherein the method comprises improving in the subject at least one of the functional efficacy endpoints selected from the group consisting of Peabody Developmental Motor Scales, Third Edition (PDMS-3) Score, Childhood Health Assessment Questionnaire (CHAQ) disability index score. Pediatric Outcomes Data Collection Instrument (PODCI), Percent 6-minute walk test (6MWT), Timed Up-and-Go (TUG). Lower Extremity Functional Scale (LEFS) Score, Muscle Strength Grade, 30-second Sit to Stand (STS) Test Score, handheld dynamometer (HHD), Bone mineral density Z-score using Dual -energy X-ray absorptiometry, Brief Pain Inventory - Short Fonn (BPI-SF) questionnaire, Bayley Scales of Infant and Toddler Development, 3rd Edition (BSID-III), Bruininks-Oseretsky Test of Motor Proficiency, Second Edition (BOT-2), and modified perfonnance-oriented mobility assessment-gait (MPOMA-G).

24. The method of any one of claims 1-15, wherein the method provides improved muscle strength or reduced pain.

25. The method of claim 24, wherein the pain is from muscle pain and / or joint pain.

26. The method of any one of claims 1-15, wherein the treatment or prevention lasts at least one year, at least two years, at least three years, at least four years, at least five years, at least six years, at least seven years, at least eight years, at least nine years, at least ten years or longer.

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