Methods of treating fibrosis

Abstract

Described herein are methods and compositions for treating fibrosis, particularly pulmonary fibrosis. The pulmonary fibrosis may be idiopathic or arise following an infection of the lung. The lung infection can be by SARS-CoV-2. Lung function stabilizes or is improved as a result of treatment.

Description

METHODS OF TREATING FIBROSISBACKGROUND

[0001] Interstitial lung diseases (ILDs) are a group of more than 200 fibrotic disorders that cause scarring in the lungs, damaging tissues in or around the lungs’ alveoli.

[0002] Idiopathic pulmonary fibrosis (IPF) and non-IPF progressive pulmonary fibrosis (PPF) are ILDs with a terminal prognosis. IPF is the most common ILD, and its origin is unknown. PPF is a subset of non-IPF fibrosing ILDs with a progressive course of disease despite conventional treatment. In the United States alone, the prevalence of IPF is estimated to be about 150,000 subjects, with an estimated 20,000 to 40,000 individuals diagnosed annually. The prevalence of PPF is about 186,000 in the United States, with an estimated 84,000 individuals diagnosed annually. The current standards of care for IPF and PPF modestly slow the decline of lung function and do not reverse the course of disease.SUMMARY

[0003] As described herein, in some embodiments, the present disclosure provides methods, compounds, and compositions for treating fibrosis or fibrotic disease using inhibitors of the hedgehog signaling pathway that are sufficiently potent and tolerable to permit clinical utilization. In some embodiments, the present disclosure provides methods of making provided compounds.

[0004] In some embodiments, the present disclosure provides methods of treating fibrosis comprising administering an inhibitor of Glil. In some embodiments, inhibition of Glil is indirect. In some embodiments, an inhibitor of SMO is used to indirectly inhibit Glil.

[0005] In some embodiments, the present disclosure provides a method of treating fibrosis comprising administering an inhibitor of Glil. In some embodiments, an inhibitor of Glil is indirect. In some embodiments, inhibitors of SMO indirectly inhibit Glil.

[0006] In some embodiments, an inhibitor of Glil is an inhibitor of SMO. In some embodiments, the present disclosure provides an inhibitor of SMO or inhibitor of Glil that is compound M75, or a pharmaceutically acceptable salt thereof:4-Fluoro-N-(l -(4-( 1 -methyl- 1 J7-pyrazol-5-yl)phthalazin- 1 -yl)piperidin-4-yl)-2-(trifluoromethyl)benzamideM75, or compound M63, or a pharmaceutically acceptable salt thereof:4-Fluoro-N-((3R,4S)-3 -hydroxy- 1 -(4-(l -methyl- I / / -pyrazol -5-yl )phthal azin- 1 -yl)piperidin-4- yl)-2-(trifluoromethyl)benzamideM63

[0007] In some embodiments, the present disclosure provides a method of treating fibrosis comprising administering a pharmaceutically effective amount of a provided compound. In some embodiments, the fibrosis is a pulmonary fibrosis. In some embodiments, the pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF). In some embodiments, the pulmonary fibrosis is pulmonary fibrosis following infection, including a bacterial or viral infection. In most instances, the pulmonary fibrosis develops after years-long chronic infections so that the role of the infection in causing the pulmonary fibrosis cannot be conclusively demonstrated; such pulmonary fibrosis is therefore still classified as idiopathic pulmonary fibrosis. Covid- 19 provides a counterpoint, in that onset of fibrosis can be very rapid. In some embodiments, the pulmonary fibrosis follows infection with SARS-CoV-2. In some embodiments, the fibrosis is scleroderma. In some instances, the fibrosis is systemic scleroderma (also known as systemic sclerosis) and in further instances, systemic scleroderma involving the lung. In some embodiments, the fibrosis is liver fibrosis, such as in non-alcoholic steatohepatitis (NASH). Insome embodiments, the fibrosis is kidney fibrosis. In some embodiments, the fibrosis is gastric fibrosis. In some embodiments, the patient is a human.

[0008] In some embodiments, the present disclosure provides a method of treating fibrosis comprising administering a provided compound in an effective amount. In some embodiments, the effective amount is effective for reducing symptoms of the fibrosis. In some embodiments, the effective amount is effective for slowing or halting progression of the fibrosis. In some embodiments, the effective amount is effective for reducing impairment due to the fibrosis. In some embodiments, the effective amount is effective for reversing impairment due to the fibrosis (causing improvement). In some embodiments, the fibrosis is pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis) and progression and / or impairment can be measured as changes in lung function, for example, as determined by spirometry. Spirometry measures that can be used include forced vital capacity (FVC), forced expiratory volume in 1 second (FEVi), and diffusion capacity of the lungs for carbon monoxide (DLco). The extent of fibrosis can also be assessed by imaging, such as high-resolution computed tomography (HRCT). In some embodiments, the effective amount comprises 25-400 mg of a provided compound. In some embodiments, the method comprises administering an initial dose of a provided compound, but upon experiencing a drug-related adverse event, the dosage is stepped down.

[0009] In some embodiments, the present disclosure provides a method of treating fibrosis comprising administering a provided compound in an effective amount. In some embodiments, the provided compound is compound M75. In some embodiments, the provided compound is compound M63.

[0010] In some embodiments, the present disclosure provides pharmaceutical compositions comprising a provided compound. In some embodiments, a pharmaceutical composition comprising a provided compound and one or more pharmaceutically acceptable carriers, diluents, or excipients. In some embodiments, a pharmaceutical composition comprising provided compounds is formulated for oral administration (e.g., as a tablet).

[0011] In some embodiments, the present disclosure provides methods for preparing provided compounds. The present disclosure also provides synthetic intermediates useful for preparing such compounds.

[0012] Two syntheses of compound M75 are described in US Patent No. 8,273,742 B2.BRIEF DESCRIPTION OF THE DRAWING

[0013] FIG. 1A, FIG. IB, and FIG. 1C depict dose-dependent GLil repression of GLil expression by taladegib, compound M75, and compound M63 at a range of doses in human Daoy tumor cell line sensitized with recombinant human Sonic hedgehog (rSHH) (200 ng / mL). Transcription levels of Glil were measured by qPCR using RLPLO as a housekeeping gene.

[0014] FIG. 2A, FIG. 2B, and FIG. 2C depict repression of GLil expression by taladegib, compound M75, and compound M63 at a range of doses in human Daoy tumor cell line sensitized with recombinant human Sonic hedgehog (rSHH) (200 ng / mL). Transcription levels of Glil were measured by qPCR using B2M as a housekeeping gene.

[0015] FIG. 3A and FIG 3B depict plasma concentration (in ng / mL) of taladegib (dotted lines with triangles), compound M75 (solid lines with circles), and compound M63 (dashed lines with squares) in human subjects being administered 200 mg / day taladegib except for a dose holiday on day 8.DESCRIPTIONDefinitions

[0016] As used herein in the present disclosure, unless otherwise clear from context, (i) the term “a” or “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising”, “comprise”, “including” (whether used with “not limited to” or not), and “include” (whether used with “not limited to” or not) may be understood to encompass itemized components or steps whether presented by themselves or together with one or more additional components or steps; (iv) the term “another” may be understood to mean at least an additional / second one or more; (v) the terms “about” and “approximately” may be understood to permit standard variation as would be understood by those of ordinary skill in the art; and (vi) where ranges are provided, endpoints are included.

[0017] Approximately: As used herein, the term “approximately” or “about,” as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term “approximately,” “approximate,” or “about” refers to a range of values that fall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (exceptwhere such number would exceed 100% of a possible value). In certain embodiments herein, the term “about” or “approximately” mean ± 10%.

[0018] Increased, Induced, or Reduced. As used herein, these terms or grammatically comparable comparative terms, indicate values that are relative to a comparable reference measurement. For example, in some embodiments, an assessed value achieved with a provided composition (e.g., a pharmaceutical composition) may be “increased” relative to that obtained with a comparable reference composition. Alternatively or additionally, in some embodiments, an assessed value achieved in a subject may be “increased” relative to that obtained in the same subject under different conditions (e.g., prior to or after an event; or presence or absence of an event such as administration of a composition (e.g., a pharmaceutical composition) as described herein, or in a different, comparable subject (e.g., in a comparable subject that differs from the subject of interest in prior exposure to a condition, e.g., absence of administration of a composition (e.g., a pharmaceutical composition) as described herein.). In some embodiments, comparative terms refer to statistically relevant differences (e.g., that are of a prevalence and / or magnitude sufficient to achieve statistical relevance). Those skilled in the art will be aware, or will readily be able to determine, in a given context, a degree and / or prevalence of difference that is required or sufficient to achieve such statistical significance. In some embodiments, the term “reduced” or equivalent terms refers to a reduction in the level of an assessed value by at least 5%, at least 10%, at least 20%, at least 50%, at least 75% or higher, as compared to a comparable reference. In some embodiments, the term “reduced” or equivalent terms refers to a complete or essentially complete inhibition, i.e., a reduction to zero or essentially to zero. In some embodiments, the term “increased” or “induced” refers to an increase in the level of an assessed value by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 80%, at least 100%, at least 200%, at least 500%, or higher, as compared to a comparable reference.

[0019] Pharmaceutically acceptable salt. The term “pharmaceutically acceptable salt”, as used herein, refers to salts of such compounds that are appropriate for use in pharmaceutical contexts, i.e., salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19(1977), incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this invention include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3- phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0020] Pharmaceutically acceptable carrier or diluent. The term “pharmaceutically acceptable carrier or diluent” refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene- polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0021] Pharmaceutical composition. As used herein, the term “pharmaceutical composition” refers to an active agent, formulated together with one or more pharmaceutically acceptable carriers. In some embodiments, the active agent is present in unit dose amount appropriate for administration in a therapeutic or dosing regimen that shows a statistically significant probability of achieving a predetermined therapeutic effect when administered to arelevant population. In some embodiments, pharmaceutical compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin, lungs, or oral cavity; intravaginally or intrarectally, for example, as a pessary, cream, or foam; sublingually; ocularly; transdermally; or nasally, pulmonary, and to other mucosal surfaces.

[0022] Subject. As used herein, the term “subject” refers to an organism to be administered with a composition described herein, e.g., for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, domestic pets, etc.) and humans. In some embodiments, a subject is a human subject. In some embodiments, a subject is suffering from a disease, disorder, or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a subject is susceptible to a disease, disorder, or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a subject displays one or more symptoms or characteristics of a disease, disorder, or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a subject displays one or more non-specific symptoms of a disease, disorder, or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a subject does not display any symptom or characteristic of a disease, disorder, or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a subject is someone with one or more features characteristic of susceptibility to or risk of a disease, disorder, or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a subject is a patient. In some embodiments, a subject is an individual to whom diagnosis and / or therapy is and / or has been administered.

[0023] Therapeutically effective amount. The term “therapeutically effective amount” or “effective dose” refers to the amount which achieves a desired reaction or a desired effect alone or together with further doses. In the case of the treatment of a particular disease (e.g., a fibrotic condition such as pulmonary fibrosis), a desired reaction in some embodiments relates to inhibition of the course of the disease (e.g., a fibrotic condition such as pulmonary fibrosis). Insome embodiments, such inhibition may comprise slowing down the progress of a disease (e.g., a fibrotic condition such as pulmonary fibrosis) and / or interrupting or reversing the progress of the disease (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, a desired reaction in a treatment of a disease (e.g., a fibrotic condition such as pulmonary fibrosis) may be or comprise delay or prevention of the onset of a disease (e.g., a fibrotic condition such as pulmonary fibrosis) or a condition (e.g., a fibrotic condition such as pulmonary fibrosis). An effective amount of a composition (e.g., a pharmaceutical composition) described herein will depend, for example, on disease (e.g., a fibrotic condition such as pulmonary fibrosis) or a condition (e.g., a fibrotic condition such as pulmonary fibrosis) to be treated, the severity of such a disease (e.g., a fibrotic condition such as pulmonary fibrosis) or a condition (e.g., a fibrotic condition such as pulmonary fibrosis), individual parameters of the patient, including, e.g., age, physiological condition, size and weight, the duration of treatment, the type of an accompanying therapy (if present), the specific route of administration and similar factors. Accordingly, doses of a composition (e.g., a pharmaceutical composition) described herein may depend on various of such parameters. In the case that a reaction in a patient is insufficient with an initial dose, higher doses (or effectively higher doses achieved by a different, more localized route of administration) may be used.

[0024] Treat or Treating. As used herein, the term “treat,” “treatment,” or “treating” refers to any method used to partially or completely alleviate, ameliorate, relieve, inhibit, prevent, delay onset of, reduce severity of, and / or reduce incidence of one or more symptoms or features of a disease, disorder, and / or condition (e.g., a fibrotic condition such as pulmonary fibrosis). Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and / or condition (e.g., a fibrotic condition such as pulmonary fibrosis). In some embodiments, treatment may be administered to a subject who exhibits only early signs of the disease, disorder, and / or condition (e.g., a fibrotic condition such as pulmonary fibrosis), for example for the purpose of decreasing the risk of developing pathology associated with the disease, disorder, and / or condition. In some embodiments, treatment may be administered to a subject at a later-stage of disease, disorder, and / or condition (e.g., a fibrotic condition such as pulmonary fibrosis).

[0025] “Fibrosis” refers to the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. Fibrosis is similar to the process called scarring, in that both involve stimulated fibroblasts laying down connective tissue, including collagen andglycosaminoglycans. The fibrosis can be initiated when immune cells such as macrophages release soluble factors that stimulate fibroblasts. The most well-characterized pro-fibrotic mediator can be TGF beta, which is released by macrophages as well as any damaged tissue between surfaces called interstitium.

[0026] Other soluble mediators of fibrosis include, but are not limited to, CTGF, platelet- derived growth factor (PDGF), and Interleukin 4 (IL-4). These molecules initiate signal transduction pathways such as the AKT / mTOR and SMAD pathways that ultimately lead to the proliferation and activation of fibroblasts, which deposit extracellular matrix into the surrounding connective tissue. This process of tissue repair can be a complex one, with tight regulation of ECM synthesis and degradation ensuring maintenance of normal tissue architecture. However, the entire process, although necessary, can lead to a progressive irreversible fibrotic response if tissue injury is severe or repetitive, or if the wound healing response itself becomes deregulated.Idiopathic Pulmonary Fibrosis

[0027] IPF is the most aggressive of interstitial lung diseases with survival of 2-3 years from time of diagnosis. IPF is a progressive fibrotic lung scarring disease that results in loss of lung elasticity, capacity, and function. Current therapeutic options are limited to drugs that modestly slow the rate of lung function decrease.

[0028] Myofibroblasts are key cellular drivers for IPF. The initial step in IPF is injury of lung alveolar epithelial cells via environmental toxins or viral infection. Patients present with IPF long after the initial injury, so this causative step involving inflammation is generally unknown and inflammation is less relevant by the time of presentation. As part of the wound healing process after initial insult, Sonic Hedgehog (SHh) is secreted. SHh activates fibroblasts and initiates epithelial mesenchymal transition (EMT) leading to production and activation of myofibroblasts in a Smo-dependent manner. Myofibroblasts secrete collagen and other extracellular matrix (ECM) proteins by which they adhere to and contract tissue, ultimately pulling the lung closed (i.e., reducing lung elasticity, capacity and function) like a wound. The action of myofibroblasts is the primary cause of IPF pathology and therefore inhibition of the Hh pathway uniquely targets the driver of IPF disease.

[0029] Myofibroblasts are derived via EMT mediated by Hedgehog or transforming growth factor (TGF) in a Hedgehog-dependent fashion. Both SHh and TGF drive differentiation of fibroblasts and other cells into myofibroblasts in a process governed by Smo. This positive feedback loop becomes dysregulated in IPF resulting in accumulation of myofibroblasts. Increased production of intracellular alpha-smooth muscle actin (aSMA) is a key characteristic of differentiated myofibroblasts and IPF fibrotic foci are rife with aSMA.

[0030] The understanding of IPF has progressed greatly over the past decade with a clear understanding that the driver of the disease is a dysregulated tissue remodeling rather than inflammation. In essence, IPF is a chronic wound with characteristics identical to a wound healing process. These are processes driven by fibroblast activation and trans differentiation of cells into myofibroblasts which deposit fibrotic extracellular matrix and contract tissue. Of great interest is the dominant pathway that governs fibroblast activation and myofibroblast accumulation, the Hedgehog (Hh) pathway through activation of Smoothened (Smo).

[0031] Inhibition of Hedgehog results in apoptosis or deactivation of myofibroblasts. SHh and activation of the Hh pathway protect myofibroblasts from apoptosis, resulting in accumulation of the cellular driver of IPF. Disruption of the Hh pathway reduces the myofibroblast production of ECM such as collagen and intracellular aSMA, both of which are required for contraction. Additionally, inhibition of Smo re-sensitizes myofibroblasts to apoptotic processes.

[0032] Hedgehog and myofibroblasts are upregulated in IPF patients. IPF patient lung samples have confirmed Hedgehog pathway components (e.g., Glil and Sonic Hedgehog (Shh)) are upregulated and that myofibroblasts are significantly infiltrated. Normal lung samples are largely devoid of Hh pathway components or myofibroblasts. IPF patient lung samples also stain very strongly for a-Smooth Muscle Actin 1 (a-SMAl) which is a marker indicative of the presence of myofibroblasts. Normal lung samples exhibit little to no staining of a-SMAl.

[0033] The general mechanism of fibrotic disease is understood to involve an initial tissue insult (the nature of which may not be apparent) causing an upregulation of a Hedgehog (Hh) signaling molecule (e.g. Sonic Hedgehog (Shh)), driving transdifferentiation of cells into myofibroblasts (that is, the conversion of differentiated cells (non-stem cells) into another type of differentiated cell, in this case myofibroblasts). The physiologic function of myofibroblastsis to repair tissue by depositing extracellular matrix and contracting tissue, as in wound closing. Fibrotic diseases, including IPF, arise from dysregulated wound remodeling involving chronic matrix deposition and tissue contraction long after initial tissue trauma may have been resolved. In some embodiments, the herein disclosed methods and compositions treat fibrotic disease by inhibiting the Hh signaling pathway so that upregulated Hedgehog can no longer drive this pathology, blocking the generation of myofibroblasts and stopping the chronic remodeling that causes fibrosis. Although this mechanism may have been clinically validated, the promise of Hh pathway inhibitors to treat fibrosis has so far not been realized, in part at least because of the toxicology profiles of certain Hh pathway inhibitors.Provided Compounds

[0034] It is disclosed herein that certain 1,4-di substituted phthalazines are potent inhibitors of SMO and the downstream transcription factors Glil and Gli2 while exhibiting a desirable toxicology profile. In some embodiments, the present disclosure provides methods of treating fibrosis comprising administering compound M75, or a pharmaceutically acceptable salt thereof:M75, or compound M63, or a pharmaceutically acceptable salt thereof:M63

[0035] In some embodiments, the present disclosure provides pharmaceutical compositions comprising compound M63 or compound M75, or pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable excipients, carriers or diluents. A "pharmaceutically acceptable carrier, diluent, or excipient" is a medium generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans.

[0036] Targeting the Hh pathway via SMO inhibition has been validated both clinically and preclinically. Hh pathway disruption to inhibit fibrosis has been demonstrated in vitro and in a number of animal models using several SMO inhibitors. These animal models have similar features that capitulate fibroblast infiltration and transdifferentiation into myofibroblasts that then drive progressive fibrosis. Inhibition of SMO is observed to disrupt fibrosis and, in some cases, reverse the disease. Additionally, it has been demonstrated that inhibition of SMO results in increased apoptosis of infiltrated myofibroblasts, reduction of a-SMAl, reduction of Glil and SHh, and reduction of collagen.

[0037] In a clinical setting, the FDA-approved SMO inhibitor, vismodegib (approved as Erivedge® for treatment of adults with metastatic BCC or locally advanced BCC), was evaluated in a single arm IPF study in combination with pirfenidone. After six months of treatment, patients on average demonstrated an increase in Forced Vital Capacity (FVC) of approximately 100 mL. Increased FVC and lung capacity have not been seen in previous clinical studies interrogating any other target considered for IPF. While SMO inhibition to disrupt the Hh pathway as a therapeutic target for IPF is validated, vismodegib is poorly tolerated by patients, as severe muscle spasms may be a significant adverse event resulting in discontinuation of over 40% of participants. This discontinuation rate is similar to the discontinuation rate experienced by patients with BCC taking vismodegib. All further developments for vismodegib as an IPF therapeutic have been discontinued.

[0038] Compound M75 and compound M63 are well-suited to target the lung compared to vismodegib. In some embodiments, a compound disclosed herein (compound M75 or compound M63) is at least 2-fold more potent, at least 3-fold more potent, at least 5-fold more potent, at least 10-fold more potent, or at least 20-fold more potent than vismodegib at inhibiting Glil (a downstream effector molecule that is expressed when the Hh pathway is activated) in the lungs. In some embodiments, potency of compounds disclosed herein at inhibiting Glil is measured in animal models such as, for example, mice or rats. In someembodiments, the clinically established maximum tolerated dose (MTD) for a compound disclosed herein (compound M75 or compound M63) is as high as 400 mg. In some embodiments, Glil mRNA inhibition by a compound disclosed herein is >85% in skin at its MTD. In some embodiments, a compound disclosed herein (compound M75 or compound M63) is evaluated clinically at a dose as low as 10 mg, as low as 25mg, as low as 50 mg, as low as 75 mg, or as low as 100 mg. In some embodiments, a compound disclosed herein is evaluated at a dose that is at least 2-fold lower, 3-fold lower, 4-fold lower, 5-fold lower, 6-fold lower, 7-fold lower, 8-fold lower, 9-fold lower, or 10-fold lower than the clinically established MTD. In some embodiments, a compound disclosed herein (compound M75 or compound M63) is evaluated clinically at a dose as low as 25 mg. In some embodiments, a compound disclosed herein is evaluated at a dose that is at least 8-fold lower than the clinically established MTD. In some embodiments, inhibition of Glil mRNA by a compound disclosed herein is greater than 80%, greater than 70%, greater than 60%, or greater than 50% at its lowest evaluated dose. In some embodiments, inhibition of Glil mRNA by a compound disclosed herein is greater than 80% at its lowest evaluated dose. In contrast, vismodegib inhibits Glil mRNA less than 25% at its MTD of 150 mg. In some embodiments, a compound disclosed herein has a better clinical safety profile than vismodegib, with substantially lower occurrence of muscle spasms (which has been observed at 80% for vismodegib). In some embodiments, administration of a compound disclosed herein results in an occurrence of muscle spasms below 60%, below 50%, below 40%, or below 30%. In some embodiments, administration of a compound disclosed herein results in an occurrence of muscle spasms of below 40%.

[0039] The compounds of the present invention are capable of reaction, for example, with a number of inorganic and organic acids to form pharmaceutically acceptable acid addition salts. Such pharmaceutically acceptable salts and common methodology for preparing them are well known in the art. See, e g., P. Stahl, et al., HANDBOOK OF PHARMACEUTICAL SALTS: PROPERTIES, SELECTION AND USE, (VCHA / Wiley-VCH, 2002); S. M. Berge, et al., “Pharmaceutical Salts,” Journal of Pharmaceutical Sciences, Vol 66, No. 1, January 1977, which is hereby incorporated by reference in its entirety. It will be appreciated that the amount of the compound disclosed herein for administration, in a dose, or in a unit dosage form (e.g., a tablet) is the amount of the free base of the compound and not the amount of a particular salt of the compound. For example, a tablet comprising “200 mg compound M75” comprises 200mg of the free base form of compound M75. If compound M75 were provided as an HC1 salt, the amount of compound M75-HC1 in a “200 mg tablet” would be about 215 mg.Pharmaceutical Compositions

[0040] The herein disclosed compounds can be formulated as pharmaceutical compositions using a pharmaceutically acceptable carrier, diluent, or excipient and administered by a variety of routes. In particular embodiments, such compositions are for oral, topical, or intravenous administration. Such pharmaceutical compositions and processes for preparing them are well known in the art. See, e.g., “Remington: The Science and Practice of Pharmacy”, 23rded., Academic Press, (2020) , which is hereby incorporated by reference in its entirety.

[0041] In some embodiments, a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, is administered as an oral dosage form, for example, as a capsule or tablet. In some embodiments, a tablet further comprises one or more pharmaceutically acceptable carriers selected from polymers, disintegrants, glidants, lubricants, coatings, binders, flavorants, film coatings, etc.

[0042] In some embodiments, a disintegrant is selected from, for example, sodium starch gycolate, sodium alginate, alginic acid, amberlite, methyl cellulose, croscarmellose sodium, combinations thereof, or the like.

[0043] In some embodiments, a glidant is selected from, for example, colloidal silica, cornstarch, talc, combinations thereof, or the like.

[0044] In some embodiments, a glidant is selected from, for example, a lubricant is selected from magnesium stearate, sodium stearyl fumarate, calcium stearate, stearic acid, zinc stearate combinations thereof, or the like.

[0045] In some embodiments, a film coating is selected from hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, polyvinyl alcohol, OP ADR Y®, combinations thereof, or the like.

[0046] In some embodiments, a binder is selected from acacia, alginic acid, methyl cellulose, carboxymethyl cellulose sodium, compressible sugar (Nu-Tab), microcrystalline cellulose, ethyl cellulose, gelatin, povidone, starch, and gums such as guar gum, tragacanth, combinations thereof, or the like.

[0047] In some embodiments, a flavorant is selected from acacia syrup, aromatic elixir, cherry syrup, cocoa syrup, orange syrup, combinations thereof, or the like.

[0048] In some embodiments, a unit dose (i.e., each dose of a compound disclosed herein (compound M75 or compound M63)) or unit dosage form contains from about 15 mg to about 1000 mg, from about 25 mg to about 750 mg, from about 50 mg to about 500 mg, from about 50 mg to about 400 mg, from about 50 mg to about 300 mg, from about 50 mg to about 250 mg, from about 100 mg to about 200 mg, from about 25 mg to about 200 mg, about 25 mg, about 35 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof.

[0049] In some embodiments, a herein disclosed compound (compound M75 or compound M63) can be formulated as tablets containing about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of the compound and one or more pharmaceutical ingredients selected from: croscarmellose sodium, HPMCAS-H, mannitol, microcrystalline cellulose, silicon dioxide, and sodium stearyl fumarate.Dosing and Clinical Safety Profile

[0050] Inhibition of Glil mRNA in skin is similar to inhibition of Glil mRNA in the lungs. Glil mRNA inhibition in skin biopsies has been measured as a surrogate for Glil mRNA inhibition in lungs in clinical studies of lung cancer. In some embodiments, nonclinical in vivo models demonstrate that the kinetics and magnitude of Glil mRNA inhibition by orally administered compound M75 or compound M63 is similar in the skin and lungs of mice. In some embodiments, the extent of Glil mRNA inhibition in the skin and lungs of mice is similar to the extent of Glil mRNA inhibition observed in the skin biopsies of human subjects being treated with clinically relevant doses.

[0051] In some embodiments, nonclinical toxicity findings for compound M75 and / or compound M63 are similar to those of approved drugs in this class. In some embodiments, important potential risks associated with on target effects of compound M75 and / or compoundM63 are hepatic injury, effects on the reproductive organs, rhabdomyolysis, reproductive toxicity and / or bone effects. In some embodiments, compound M75 and / or compound M63 do not result in the class effect amenorrhea.

[0052] Clinically, the mean half-life (t%) across all doses is estimated to be approximately 16 hours for compound M75, allowing for once daily dosing. Median tmax is estimated to be 2 hours.

[0053] The relationship between the efficacy and toxicity of a drug is generally expressed in terms of therapeutic window and therapeutic index. Therapeutic window is the dose range from the lowest dose that exhibits a detectable therapeutic effect up to the maximum tolerated dose (MTD); the highest dose that will exhibit the desired therapeutic effect without producing unacceptable toxicity. Most typically therapeutic index is calculated as the ratio of LDso EDso when based on animal studies and TDso EDso when based on studies in humans (though this calculation could also be derived from animal studies and is sometime called the protective index), where LD50, TD50, and ED50 are the doses that are lethal, toxic, and effective in 50% of the tested population, respectively.

[0054] In various aspects of these embodiments the toxicity is an observable toxicity, a substantial toxicity, a severe toxicity, or an acceptable toxicity, or a dose-limiting toxicity (such as but not limited to a MTD). By an observable toxicity it is meant that while a change is observed the effect is negligible or mild. By substantial toxicity it is meant that there is a negative impact on the patient’s overall health or quality of life. In some instances, a substantial toxicity may be mitigated or resolved with other ongoing medical intervention. By a severe toxicity it is meant that the effect requires acute medical intervention and / or dose reduction or suspension of treatment. The acceptability of the toxicity will be influenced by the particular disease being treated and its severity and the availability of mitigating medical intervention.

[0055] Toxicities and adverse events are sometimes graded according to a 5 point scale. A grade 1 or mild toxicity is asymptomatic or induces only mild symptoms; may be characterized by clinical or diagnostic observations only; and intervention is not indicated. A grade 2 or moderate toxicity may impair activities of daily living (such as preparing meals, shopping, managing money, using the telephone, etc.) but only minimal, local, or non-invasive interventions are indicated. Grade 3 toxicities are medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization is indicated; activities ofdaily living related to self-care (such as bathing, dressing and undressing, feeding oneself, using the toilet, taking medications, and not being bedridden) may be impaired. Grade 4 toxicities are life-threatening and urgent intervention is indicated. Grade 5 toxicity produces an adverse event-related death. Thus, in various embodiments, use of a drug in the herein disclosed regimen or dosage reduces the grade of a toxicity associated with treatment by at least one grade as compared to use of that drug according to another regimen. In other embodiments, by use of a drug according to a specified regimen or dosage, a toxicity is confined to grade 2 or less, grade 1 or less, or produces no observation of the toxicity. In some embodiments, a therapeutic index of a herein disclosed inhibitor of Glil or SMO is greater than that of vismodegib (approximately 0.37). In some embodiments, a therapeutic index of a compound disclosed herein is greater than that of vismodegib. In comparison, the therapeutic index of a compound disclosed herein may be approximately 8. In some embodiments, a therapeutic index of a compound disclosed herein may be greater than 1, 2, 3, 4, 5, 6, or 7. In some embodiments, the therapeutic index of compound M75 may be approximately 8. In some embodiments, a therapeutic index of compound M75 may be greater than 1, 2, 3, 4, 5, 6, or 7. In some embodiments, the therapeutic index of compound M63 may be approximately 8. In some embodiments, a therapeutic index of compound M63 may be greater than 1, 2, 3, 4, 5, 6, or 7.Methods of Treatment

[0056] In some embodiments, the present disclosure provides a method of treating pulmonary fibrosis, the method comprising administering compound M75, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some such embodiments, the method comprises administering a therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof. In some such embodiments, a therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 10-200 mg. In some such embodiments, a therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 100-200 mg. In certain embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 100 mgadministered once a day. In certain embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 150 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 200 mg administered once a day.

[0057] In some embodiments, the present disclosure provides a method of treating pulmonary fibrosis, the method comprising administering compound M63, or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some such embodiments, the method comprises administering a therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof. In some such embodiments, a therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 10-200 mg. In some such embodiments, a therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 100-200 mg. In certain embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 100 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 150 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 200 mg administered once a day.

[0058] In some embodiments, the present disclosure provides a method of improving lung function in a subject suffering from or diagnosed with pulmonary fibrosis, for example, idiopathic pulmonary fibrosis (IPF) or non-IPF progressive pulmonary fibrosis (PPF), the method comprising administering compound M75, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the method comprises administering atherapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof. In some such embodiments, a therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 10-200 mg. In some such embodiments, a therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 100-200 mg. In certain embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 100 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 150 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, the therapeutically effective amount of compound M75, or a pharmaceutically acceptable salt thereof, is about 200 mg administered once a day.

[0059] In some embodiments, the present disclosure provides a method of improving lung function in a subject suffering from or diagnosed with pulmonary fibrosis, for example, idiopathic pulmonary fibrosis (IPF) or non-IPF progressive pulmonary fibrosis (PPF), the method comprising administering compound M63, or a pharmaceutically acceptable salt thereof, to the subject. In some such embodiments, the method comprises administering a therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof. In some such embodiments, a therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 10-200 mg. In some such embodiments, a therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 100-200 mg. In certain embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 100 mg. In some embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 100 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 150 mg. In some embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 150 mg administered once a day. In certain embodiments, the therapeutically effective amount of compound M63,or a pharmaceutically acceptable salt thereof, is about 200 mg. In some embodiments, the therapeutically effective amount of compound M63, or a pharmaceutically acceptable salt thereof, is about 200 mg administered once a day.

[0060] In some embodiments, the improvement in lung function is continuous improvement during the treatment period (i.e., during the period in which the subject is administered a compound disclosed herein). In some embodiments, the improvement in lung function is maintained or persists after the treatment period (i.e., after the period in which the subject was administered a compound disclosed herein).

[0061] In some embodiments, the improvement in lung function is determined by an improvement in forced vital capacity (FVC) as compared to baseline FVC (e.g., a change from baseline of FVC measured in mL at week 12). In some embodiments, the present disclosure provides a method of increasing forced vital capacity in a subject in need thereof, the method comprising administering therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the forced vital capacity is increased by about 40mL, about 50mL, about 60mL, about 70mL, about 80mL, about 90mL or about lOOmL. In some embodiments, the forced vital capacity is increased by at least 40mL, at least 50mL, at least 60mL, at least 70mL, at least 80mL, at least 90mL, or at least 100mL. In some embodiments, the forced vital capacity (FVC) is percent predicted forced vital capacity (ppFVC).

[0062] In some embodiments, the improvement in lung function is determined by improvement in diffusion capacity of the lungs for carbon monoxide (DLco) as compared to baseline DLco (e.g., a change from baseline in DLco, e.g., as measured at week 12).

[0063] In some embodiments, the improvement in lung function is determined by patient- reported outcomes, for example, as those reported by patients on the University of California San Diego Shortness of Breath Questionnaire (UCSD SOBQ) at, for example, week 12).

[0064] In some embodiments, the improvement in lung function is determined by quantitative measurements or qualitative measurements.

[0065] In some embodiments, the improvement in lung function is determined by an increase in total lung capacity (TLC) as compared to baseline TLC. In some such embodiments, the improvement in lung capacity (TLC) is measured by high resolution CT (HRCT). In some embodiments, the present disclosure provides a method of increasing total lung capacity byabout 5%, about 6%, about 7%, about 8%, about 9%, about 10%, about 11%, about 12%, about 13%, about 14%, or about 15% from baseline, the method comprising administering a therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of increasing total lung capacity by at least 5%, at least 6%, at least 7%, at least 8%, at least 9%, at least 10%, at least 11%, at least 12%, at least 13%, at least 14%, or at least 15% from baseline, the method comprising administering therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0066] In some embodiments, the present disclosure provides a method of increasing total lung capacity by about 50mL, about 75mL, about lOOmL, about 125mL, about 150mL, about 175mL, about 200mL, about 225mL, about 250mL, about 275mL, or about 300mL from baseline, the method comprising administering therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof. In some embodiments, the present disclosure provides a method of increasing total lung capacity by at least 50mL, at least 75mL, at least lOOmL, at least 125mL, at least 150mL, at least 175mL, at least 200mL, at least 225mL, at least 250mL, at least 275mL, or at least 300mL from baseline, the method comprising administering therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof.

[0067] In some embodiments, the improvement in lung function is determined by a reduction in one or measures of lung fibrosis. In some embodiments, the one or more measures of fibrosis are selected from percent quantitative lung fibrosis (%QLF), percent ground glass opacity, or percent honeycombing.

[0068] In some embodiments, the present disclosure provides a method of improving quantitative lung fibrosis (QLF) in a subject in need thereof, the method comprising administering therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the subject experiences a change from baseline %QLF of about -0.5%, about -0.6%, about -0.7%, about -0.8%, about -0.9%, about -1.0%, about -1.1%, about -1.2%, about-1.3%, about -1.4%, about -1.5%, about -1.6%, about -1.7%, about -1.8%, about -1.9%, about -2.0%, about -2.1%, about -2.2%, about -2.3%, about -2.4%, about -2.5%, about -2.6%, about -2.7%, about -2.8%, about -2.9%, or about -3.0%. In some embodiments, the subject experiences a change from baseline %QLF of at least -0.5%, at least -0.6%, at least -0.7%, at least -0.8%, at least -0.9%, at least -1.0%, at least -1.1%, at least -1.2%, at least -1.3%, at least -1.4%, at least -1.5%, at least -1.6%, at least -1.7%, at least -1.8%, at least -1.9%, at least -2.0%, at least -2.1%, at least -2.2%, at least -2.3%, at least -2.4 at least -2.5%, at least -2.6%, at least -2.7%, at least -2.8%, at least -2.9%, at least -3.0%.

[0069] In some embodiments, the present disclosure provides a method of improving or reducing percent quantitative interstitial lung disease (%QILD) in a subject in need thereof, the method comprising administering therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the subject experiences a change from baseline %QILD of about -0.5%, about -1.0%, about -1.5%, about -2.0%, about -2.5%, about -3.0%, about -3.5%, about -4.0%, about -4.5%, about -5.0%, about -5.5%, about -6.0%, about -6.5%, about -7.0%, about -7.5%, about -8.0%, about -8.5%, about -9.0%, about -9.5%, about -10.0%, about -10.5%, about -11.0%, about -11.5%, about -12.0%, about -12.5%, or about -13.0%. In some embodiments, the subject experiences a change from baseline %QILD of at least -0.5%, at least-1.0%, at least -1.5%, at least -2.0%, at least -2.5%, at least -3.0%, at least -3.5%, at least-4.0%, at least -4.5%, at least -5.0%, at least -5.5%, at least -6.0%, at least -6.5%, at least-7.0%, at least -7.5%, at least -8.0%, at least -8.5%, at least -9.0%, at least -9.5%, at least-10.0%, at least -10.5%, at least -11.0%, at least -11.5%, at least -12.0%, at least -12.5%, or at least -13.0%.

[0070] In some embodiments, the present disclosure provides a method of improving percent quantitative ground glass opacity (%QGG) in a subject in need thereof, the method comprising administering a therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to the subject. In some embodiments, the subject experiences a change from baseline %QGG of about -0.5%, about -1.0%, about -1.5%, about -2.0%, about -2.5%, about -3.0%, about -3.5%, about -4.0%, about -4.5%, about -5.0%, about -5.5%, about -6.0%, about -6.5%, about -7.0%, about -7.5%, about -8.0%, about -8.5%, about -9.0%, about -9.5%, or about -10.0%. In some embodiments, the subject experiences a percent change from baseline QGG of at least -0.5%, at least -1.0%, atleast -1.5%, at least -2.0%, at least -2.5%, at least -3.0%, at least -3.5%, at least -4.0%, at least -4.5%, at least -5.0%, at least -5.5%, at least -6.0%, at least -6.5%, at least -7.0%, at least -7.5%, at least -8.0%, at least -8.5%, at least -9.0%, at least -9.5%, or at least -10.0%.

[0071] In some embodiments, the improvement in lung function is measured by quantitative appearance such as reduction in scarring of the lung tissue or reduction in remodeling of the lung tissue as measured by an imaging technique such as CT scan or MRI.

[0072] In some embodiments, the present disclosure provides a method of treating pulmonary fibrosis, the method comprising administering a therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof once a day for at least 4 weeks, at least 8 weeks, at least 12 weeks, at least 16 weeks, at least 20 weeks, at least 24 weeks, or longer. In some embodiments, compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, is administered to the subject until the symptoms of pulmonary fibrosis completely resolve or until symptoms of pulmonary fibrosis substantially resolve.

[0073] In some embodiments, a subject administered a therapeutically effective amount of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, does not experience any grade 4 adverse events. In some embodiments, a subject administered a compound disclosed herein (compound M75 or compound M63) does not experience any grade 3 or grade 4 adverse events.

[0074] In some embodiments, the present disclosure provides a method comprising: a. administering an initial dose of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof; and b. if the subject experiences one or more adverse events, decreasing the dose of a compound disclosed herein (compound M75 or compound M63) (i.e., a “stepdown dose”).

[0075] In some embodiments, the subject is administered a step-down dose until the adverse event resolves. In some embodiments, the subject resumes the initial dose (e.g., 200 mg) once the adverse event has resolved. In some embodiments, an initial dose is 50 mg, 75 mg, 100mg, 125 mg, 150 mg, 175 mg, or 200 mg. In some embodiments, a step-down dose is 25 mg. In some embodiments, a step-down dose is 50 mg. In some embodiments, a step-down dose is 75 mg. In some embodiments, a step-down dose is 100 mg. In some embodiments, a stepdown dose is 125 mg. In some embodiments, a step-down dose is 150 mg. In some embodiments, a step-down dose is 175 mg.

[0076] In some embodiments, the present disclosure provides a method comprising: a. administering an initial dose of a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject in need thereof; and b. if the subject experiences one or more adverse events, decreasing the dose of a compound disclosed herein (compound M75 or compound M63) to a first step-down dose.

[0077] In some embodiments, if the subject continues to experience one or more adverse events, further decreasing the dose of a compound disclosed herein (compound M75 or compound M63) to a second step-down dose. In some embodiments, a first step-down dose is half of the initial dose, and the second step-down dose is half of the first step-down dose. For example, in some embodiments, an initial dose is 200 mg, a first step-down dose is 100 mg, and a second step-down dose is 50 mg. In some embodiments, a first step-down dose is a 50 mg decrement, and the second dose is a further 50 mg decrement. For example, in some embodiments, an initial dose is 200 mg, a first step-down dose is 150 mg, and a second stepdown dose is 100 mg. In some embodiments, a first step-down dose is 150 mg. In some embodiments, a second step-down dose is 100 mg. In some embodiments, if the subject is administered a first step-down dose, the subject resumes the initial dose (e.g., 200 mg) once the adverse event resolves. In some embodiments, if the subject is administered a second stepdown dose, the subject resumes the first step-down dose for a period of time sufficient to ensure that the one or more adverse events do not resume. In some embodiments, the subject resumes the first step-down dose for a period of 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, or 8 weeks.

[0078] In some embodiments, the dosage of compound M75, compound M63, or pharmaceutically acceptable salts thereof, is begun at 200 mg / day. In some embodiments, the dosage is provided in a single daily dose. If grade 3 or higher AEs are observed, dosing isstepped down. In some embodiments, the dosage is stepped down in decrements of 25 mg / day as needed to avoid grade 3 or higher AEs, to as little as 25 mg / day. In some embodiments, an initial dosage (before step-down) can be any dosage higher than the lowest dosage deemed an effective dose. In some embodiments, the initial dosage in is the top half of the effective dose range. In some embodiments, the initial dosage is at the top of the effective dose range. For example, if the effective dose range is in 25-200 mg, an initial dose could be >50 mg (e.g., 75 mg), 125-200 mg, or 200 mg. In some instances, the initial dosage is in a range of 100-300 mg / day. In some instances, the step-down in dosage is 25, 50, or 100 mg / day.

[0079] In some embodiments, an effective dose of the inhibitor of Glil or SMO, or means for inhibiting Glil or SMO results in stabilization or improvement of fibrosis, such as with respect to the physical extent of fibrosis, lung function, or other measure as described herein. In further embodiments, the stabilization or improvement of fibrosis is achieved without the patient experiencing drug-related adverse events (toxicities). In particular instances, the avoided drug-related adverse events are grade 3 or higher toxicities. In some embodiments, the absent drug-related adverse events are muscle spasms, QT elongation or a liver toxicity.

[0080] Various aspects are methods of treating fibrosis by administering an inhibitor of Glil or SMO, or means for inhibiting Glil or SMO, to a patient in need thereof, that is, a patient having a fibrotic disease. In some embodiments, the inhibitor of Glil or SMO, or means for inhibiting Glil or SMO is used as monotherapy. In some embodiments, the inhibitor of Glil or SMO, or means for inhibiting Glil or SMO is used in combination with another anti -fibrosis drug. In some embodiments, the other anti-fibrosis drug is not a Hh pathway inhibitor. In some instances, the non-Hh pathway inhibitor anti-fibrosis drug is pirfenidone, nintedanib, GLPG4716 or PRM-151.

[0081] In some embodiments, the fibrotic disease is idiopathic pulmonary fibrosis (IPF). In some embodiments, the fibrotic disease is pulmonary fibrosis following infection, including a bacterial or viral infection. In most instances, the fibrosis develops after years-long chronic infections so that the role of the infection in causing the fibrosis cannot be conclusively demonstrated; such fibrosis is therefore still classified as idiopathic. Covid- 19 provides a counterpoint, in that onset of fibrosis can be very rapid. In some embodiments, the pulmonary fibrosis follows infection with SARS-CoV-2. In some embodiments, the fibrotic disease is scleroderma. In some instances, the fibrotic disease is systemic scleroderma (also known assystemic sclerosis) and in further instances, systemic scleroderma involving the lung. In some embodiments, the fibrotic disease is liver fibrosis, such as in non-alcoholic steatohepatitis (NASH). In some embodiments, the fibrotic disease is kidney fibrosis, for example, renal interstitial fibrosis or renal allograft fibrosis. In some embodiments, the fibrotic disease is gastric fibrosis, for example, gastric mucosal fibrosis, glandular stomach fibrosis, or retroperitoneal fibrosis. In some embodiments, the patient is a human. In some embodiments, the patient is a non-human animal, for example a mammal.

[0082] In some embodiments, provided methods comprise administering to a subject who is not concurrently exposed to one or more agents selected from N-acetylcysteine, an endothelin receptor antagonist, riociguat, prostacyclin or a prostacyclin analog, warfarin, a cytotoxic agent (e.g., colchicine), radiation to the lungs, an immunosuppressive agent (e.g., methotrexate, azathioprine, etc.), a glucocorticosteroid, and an antifibrotic agent (e.g., nintedanib, pirfenidone, etc.).

[0083] In some embodiments, provided methods comprise administering a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject who has previously been treated with nintedanib (Ofev®) or pirfenidone (Esbriet®). In some embodiments, provided methods comprise administering a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, to a subject who has not been previously treated with nintedanib (Ofev®) or pirfenidone (Esbriet®). In some embodiments, a subject treated with a compound disclosed herein (compound M75 or compound M63) does not have confirmed active human immunodeficiency virus (HIV), Hepatitis B virus (HBV) or Hepatitis C virus (HCV).

[0084] In some embodiments, a subject treated with a compound disclosed herein (compound M75 or compound M63), or a pharmaceutically acceptable salt thereof, is not concurrently exposed to a moderate or strong CYP3A4 inhibitor. In some embodiments, a moderate inhibitor of CYP3A4 is selected from amiodarone, erythromycin, fluconazole, miconazole, diltiazem, verapamil, delavirdine, amprenavir, fosamprenavir, and conivaptan, among others. In some embodiments, a strong CYP3 A4 inhibitor is selected from boceprevir, clarithromycin, conivaptan, grapefruit juice, itraconazole, ketoconazole, indinavir, lopinavir / ritonavir combination, mibefradil, nefazodone, nelfinavir, Posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, and voriconazole, among others.

[0085] For each method of treatment, there are parallel embodiments expressed as use of a compound disclosed herein in the treatment of a fibrotic disease, or its use in the manufacture of a medicament for the treatment of a fibrotic disease, or a composition or pharmaceutical composition for use in treating a fibrotic disease, and the like.

[0086] Treatment efficacy or benefit for pulmonary fibrosis is commonly assessed by changes in lung function for example, as determined by spirometry. Spirometry measures that can be used include forced vital capacity (FVC), forced expiratory volume in 1 second (FEVi), and diffusion capacity of the lungs for carbon monoxide (DLco). Further spirometry parameters that can be considered include FEVi / FVC ratio, observed FVC as a percentage of predicted FVC (FVC % predicted), and observed FEVi as a percentage of predicted FEVi (FEVi % predicted). The predicted value of FVC (in liters) as published by the Association for Respiratory Technology and Physiology is 5.76*height (in meters) - 0.026*age (in years) - 4.34. The predicted value of FEVi (in liters) as published by the Association for Respiratory Technology and Physiology is 4.30*height (in meters) - 0.029*age (in years) - 2.49.

[0087] Other assessments include:• appearance of the lungs - quantitative extent of fibrosis (including scarring or remodeling), by percent and / or volume, as determined by CT scan, magnetic resonance imaging (MRI), and the like;• appearance of the lungs - qualitative extent of fibrosis: improved, same, or worse), as determined by CT scan, magnetic resonance imaging (MRI), and the like;• the number of respiratory hospitalizations;• the distance that can be walked in a set interval of time, for example, 6-minute walk distance; and• scores on a respiratory health questionnaire, for example, St. George’s Respiratory Questionnaire, the UCSD Shortness of Breath Questionnaire, and the like. Assessments.

[0088] The spirometry and other assessments may be made at regular intervals, for example, about every 24 weeks, quarterly, semi-annually, or annually.

[0089] Treatment efficacy or benefit may be observed as a decrease in the progression of the disease, a stabilization of the disease, or improvement in the patient’s condition. In some embodiments, progression, stabilization, or improvement is judged in comparison to a previous measurement or measurements of that patient. In some embodiments, the previous measurement is a baseline measurement prior to initiation of treatment. In some embodiments, progression, stabilization, or improvement is judged based in comparison with other patients, actual or historical, receiving no treatment, placebo, or alternative treatment. Thus, in some embodiments, improvement or stabilization is judged by comparison to what would be expected in an untreated patient. For example, in such embodiments, decreased scarring includes an increase in scarring that is less than would be expected in an untreated patient. Thus, a stabilization of lung function does not imply no further decrease in one or another measure of lung function but rather that any decrease does not exceed that expected with aging for the time interval considered.Enumerated Embodiments1. A compound, which is compound M63:or a pharmaceutically acceptable salt thereof.2. A pharmaceutical composition comprising the compound of Embodiment 1 and one or more pharmaceutically acceptable carriers, diluents, or excipients.3. The pharmaceutical composition of Embodiment 2, wherein the composition is formulated for oral administration.4. The pharmaceutical composition of Embodiment 3, wherein the composition is formulated as a tablet.5. The pharmaceutical composition of Embodiment 4, wherein the tablet comprises an amount of the compound between about 25 mg and about 400 mg.6. The pharmaceutical composition of Embodiment 5, wherein the tablet comprises an amount of the compound selected from about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, and about 400 mg.7. The pharmaceutical composition of Embodiment 2, wherein the composition is formulated for topical administration.8. A pharmaceutical composition comprising a compound, wherein the compound is compound M75:or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.9. The pharmaceutical composition of Embodiment 8, wherein the composition is formulated for oral administration.10. The pharmaceutical composition of Embodiment 9, wherein the composition is formulated as a tablet.11. The pharmaceutical composition of Embodiment 10, wherein the tablet comprises an amount of the compound between about 25 mg and about 400 mg.12. The pharmaceutical composition of Embodiment 11, wherein the tablet comprises an amount of the compound selected from about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, and about 400 mg.13. The pharmaceutical composition of Embodiment 8, wherein the composition is formulated for topical administration.14. A method of treating fibrosis comprising administering a therapeutically effective amount of a compound, wherein the compound is compound M75:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.15. A method of treating fibrosis comprising administering a therapeutically effective amount of a compound, wherein the compound is compound M63:or a pharmaceutically acceptable salt thereof, to a patient in need thereof.16. The method of Embodiment 14 or Embodiment 15, comprising administering between about 25 mg and about 400 mg of the compound.17. The method of Embodiment 16, comprising administering between about 25 mg / day and about 400 mg / day of the compound.18. The method of Embodiment 16, comprising administering about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of the compound.19. The method of Embodiment 18, comprising administering about 25 mg / day, about 50 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, or about 400 mg / day of the compound.20. The method of Embodiment 14 or Embodiment 15, wherein an initial dosage of between about 100 mg and about 300 mg is administered, but upon the patient experiencing a drug-related adverse event, the dosage is stepped down.21. The method of any one of Embodiments 14-20, wherein the fibrosis is idiopathicpulmonary fibrosis.22. The method of any one of Embodiments 14-21, wherein the fibrosis is pulmonary fibrosis following a pulmonary infection.23. The method of Embodiment 22, wherein the pulmonary infection is infection by SARS-CoV-2.24. The method of any one of Embodiments 14-21, wherein the fibrosis is systemic scleroderma.25. The method of any one of Embodiments 14-24, wherein the subject does not experience an adverse event of grade 3 or greater.26. The method of any one of Embodiments 14-25, wherein fibrosis does not progress after initiation of treatment.27. The method of any one of Embodiments 14-23 or 25-26, wherein the fibrosis is a pulmonary fibrosis and the subject experiences a stabilization of lung function.28. The method of any one of Embodiments 14-23 or 25-26, wherein the fibrosis is a pulmonary fibrosis and the subject experiences improvement of lung function.29. The method of any one of Embodiments 14-23 or 25-28, wherein the fibrosis is a pulmonary fibrosis and the subject experiences a decrease in scarring.30. A method of treating fibrosis comprising administering a compound of Formula 1 to a patient in need thereof:Formula 1.31. A method of treating fibrosis comprising administering a compound of Formula 2 to a patient in need thereof:Formula 2.32. The method of Embodiment 30 or Embodiment 31 comprising administering 25-200 mg of the compound of Formula 1 or Formula 2.33. The method of Embodiment 32, wherein an initial dosage of 100-300 mg is administered but upon the patient experiencing a drug-related adverse event, the dosage is stepped down.34. The method of any one of Embodiments 30-32, wherein the fibrosis is idiopathic pulmonary fibrosis.35. The method of any one of Embodiments 30-32, wherein the fibrosis is systemic scleroderma.36. The method of any one of Embodiments 30-32, wherein the fibrosis is pulmonary fibrosis following a pulmonary infection.37. The method of Embodiment 36, wherein the pulmonary infection is infection by SARS-CoV-2.38. The method of any one of Embodiments 30-37, wherein toxicity is confined to grade 2 or less.39. The method of any one of Embodiments 30-38, wherein fibrosis does not progress after initiation of treatment.40. The method of any one of Embodiments 30-32, wherein the fibrosis is a pulmonary fibrosis and lung function is stabilized.41. The method of any one of Embodiments 30-32, wherein the fibrosis is a pulmonary fibrosis and lung function is improved.42. The method of any one of Embodiments 30-32, wherein the fibrosis is a pulmonary fibrosis and scarring is decreased.43. A compound having the structure of Formula 2:EXAMPLES

[0090] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples should not be construed to limit any of the embodiments described in the present specification.Example 1In Vitro Pharmacology of Provided Compounds

[0091] Using an in vitro competitive binding assay, half-maximal inhibitory concentration (IC50) and binding constant (Ki) are calculated based on the competitive displacement of a radioligand. The binding of compound M75 and compound M63 to hSMO receptor is observed and their ability to inhibit binding of3H-2406189 (a known hSMO agonist) to hSMO is measured to determine their respective Ki and IC50 values.

[0092] To determine the biological activity of compound M75 and compound M63 in mouse cells, Gli-Luciferase activity is quantified in a mouse mesenchymal CSHIOTU cell line stimulated with sonic hedgehog conditioned media (SHh-CM). Compound M75 and compound M63 are observed to inhibit Hh signaling activity in mouse CSHIOTU cells and the IC50 values of their inhibitory effects are quantified.

[0093] To determine the biological activity of compound M75 and compound M63 in human cells, Glil transcript levels are quantified in a human Daoy tumor cell line stimulated with SHh-CM. Compound M75 and compound M63 are observed to inhibit Hh signaling activity in human Daoy cells and the IC50 values are determined by measurement of Glil mRNA using branched chain deoxyribonucleic acid (DNA) assay technology.

[0094] The in vitro potency of taladegib, compound M75, and compound M63, was assessed by quantifying Glil expression levels through qPCR.

[0095] Daoy cells (selected as a model system as the Hh signaling pathway is highly active) were cultured in complete medium to 75-80% confluency in a T75 flask. The culture medium was removed, and the cell layer rinsed with sterile PBS. Trypsin-EDTA solution (3.0mL) was added, and the flask incubated at 37°C for 5 minutes. Complete medium (7.0mL) was added. The cells were pipetted into 15mL tubes, centrifuged at 125g for 5 minutes and then counted. Cells in assay medium (lOOuL) were dispensed into 12-well plates (0.1 million cells per well) and placed in an incubator at 37°C overnight, taladegib, compound M75, and compound M63 were serial diluted in DMSO to provide final concentrations of luM, 0.3uM, O. luM, 30nM, lOnM, 3nM, InM and O.lnM (n=3 for each group). Wells were conditioned with recombinant Sonic Hedgehog (rSHH, + / - 200ng / mL, PeproTech Cat# 100-45) and taladegib, compound M75, compound M63, or DMSO and then the samples were placed in an incubator at 37°C for 24 hours. Each well was washed with sterile PBS (3x), and then frozen at -80°C overnight. Samples were processed for RNA extraction using RNeasy Mini Kit (Qiagen Cat# 74104) and RNA concentrations were measured using Nanodrop. The i Script Reverse Transcription Supermix (Cat#1708841) protocol was followed to construct cDNA (lug RNA was used to construct cDNA). SYBR Green based qPCR was run with GLI1, using RLPL0 as a housekeeping gene. Complete medium contained EMEM (ATCC Cat# 30-2003), 10% FBS and 1% Pen / Strep and assay medium contained EMEM (500mL), B-27 50x (Thermofisher Scientific Cat# 17504044), and 1% Pen / Strep.

[0096] Taladegib, compound M75, and compound M63 repressed Glil mRNA expression, was measured by semi-quantitative PCR (qPCR), see FIG. 1A, FIG. IB and FIG. 1C, respectively. Using the built-in non-linear regression function in GraphPad Prism, ECso values were generated:Taladegib: 4.5 nMCompound M75: 8.7 nMCompound M63: 33 nM.

[0097] Taladegib, compound M75, and compound M63 repression of Glil and B2M (Housekeeping gene) mRNA expression were measured in Daoy cells that were plated overnightbefore conditioning in medium containing rSHH(200ng / mL) and the tested agent, see FIG. 2A, FIG. 2B and FIG. 2C, respectively.Example 2In Vivo Pharmacology of Provided Compounds

[0098] Key PK / PD studies involving dose response and time course are carried out following a single oral administration of the compound M75 or compound M63 in Balb / c surrogate and PTCH / +x p53' / _tumor models. Following the predetermined dosing period, surrogate tissues(lung, skin, and cerebellum) from Balb / C mouse and tumor from Ptch x p53 transgenic tumor model are harvested, processed, and evaluated for Glil expression levels using a quantitative reverse transcription polymerase chain reaction TaqMan® assay.

[0099] The details and results of taladegib PK experiments conducted on rats and dogs are presented in the tables below.

[0100] Two human subjects (subject 1 : weight = 79 kg / BMI = 26.6; subject 1 : weight = 100 kg / BMI = 32.6) were dosed with 200 mg / day taladegib for 10 days with a dose holiday on day 8. Measurements of plasma concentrations of taladegib, compound M75, and compound M63 are provided in the table below and in FIG. 3A and FIG. 3B.*Below Quantification Limit**Dose holidayExample 3Reduction of Myofibroblasts in Bleomycin-Induced Pulmonary Fibrosis Model

[0101] The Bleomycin (BLM) induced pulmonary fibrosis model is a standard IPF model, widely used in pharmacology and fundamental research. In IPF patients, loss of lung function is driven by the infiltration and expansion of activated myofibroblasts. A Microsprayer® Aerosolizer is used to perform intratracheal administration of bleomycin. By administering bleomycin via Microsprayer® Aerosolizer, it can be evenly exposed to the lungs and thus, resulting in the development of a reproducible and uniform pathology. In this model, thepresence of myofibroblasts is observed by immunohistochemistry when stained with anti- alpha-smooth muscle actin (a-SMA) antibodies.

[0102] Animals are exposed to bleomycin and then treated with compound M75 or compound M63 at the onset of fibrosis on day seven. Pathology of the animals is examined on day 21 of the study. Treatment with compound M75 or compound M63 at 5mg / kg orally administered daily results in a reduction of a-SMA protein expression indicating a reduction of myofibroblasts.Example 4Study Evaluating the Safety and Efficacy of Provided Compounds in subjects with IPF

[0103] Patients diagnosed with IPF based upon American Thoracic Association, Japanese Respiratory Society, European Respiratory Society, Latin American Thoracic Association guidelines, and confirmed by high resolution computed tomography (HRCT), having percent predicted FVC of >50% and percent predicted DLCO between 35% and 85%, are randomized into compound M75 and / or compound M63 and placebo groups. Baseline results from lung function tests (FVC, FEVi and DLco), HRCT, and the UCSD Shortness of Breath (SOB) questionnaire are obtained. Compound M75 or compound M63 is administered daily for 12 weeks, starting at 200 mg / day. The patients are observed an additional 6 weeks after the scheduled treatment is completed. If medication-related adverse events are experienced, the dosage may be reduced to as little as 100 mg / day. Lung function tests and the UCSD SOB questionnaire are administered again at weeks 6, 12, and 18 of the study. HRCT is repeated at 12 weeks. Efficacy is assessed by change from baseline for FVC, FEVi, FEVi / FVC ratio, FVC % predicted, FEVi % predicted, and DLco and the UCSD SOB questionnaire at weeks 6, 12, and 18. Quantitative (% and mL) and qualitative (improved, same, worse) assessment of lung fibrosis by HRCT will be performed at Screening and Week 12. The Screening HRCT will serve as the baseline for study HRCT assessments. At 12 weeks, no or limited dose limiting toxicities are observed. At 12 weeks, some efficacy endpoints demonstrate stabilization or improvement. At 18 weeks, durability of the response is observed. Patients do not experience serious drug-related adverse events (after sufficient step-down of dosage, if any), including the absence of muscle spasms.Example 5Covid-19 therapy clinical trial

[0104] Patients recovered from SARS-CoV-2 infection showing lung fibrosis by CT scan are randomized for treatment with standard of care, compound M75 monotherapy, or M63 monotherapy. Compound M75 or compound M63 is administered daily starting at 200 mg. If medication-related adverse events are experienced, the dosage may be reduced in steps of 100 mg to reduce or eliminate adverse events. Pharmacokinetic data is collected. The primary efficacy endpoint is FVC change from baseline at 24 weeks. Secondary efficacy endpoints change in lung fibrosis from baseline CT scan, change from baseline in 6-minute walk distance, the number of adjudicated respiratory hospitalizations, and change from baseline in St. George’s Respiratory Questionnaire. At 24 weeks some efficacy endpoints demonstrate stabilization or improvement. Patients do not experience serious drug-related adverse events (after sufficient step-down of dosage, if any), including the absence of muscle spasms.Example 6Synthesis of 4-Fluoro-N-(3-hydroxy-l-(4-( 1 -methyl- 1 J / -pyrazol-5-yl)phthalazin- 1- yl)piperidin-4-yl)-2-(trifluoromethyl)benzamide (Compound M63)

[0105] The synthesis of compound M63 was carried out using the following procedure according to the scheme laid out below.

[0106] Step 1 Tert-butyl (3R,4S)-4-(4-fhioro-2-(trifhioromethyl)benzamido)-3- hydroxypiperidine- 1 -carboxylate (compound 9-a). TEA (351 mg, 3.5 mmol) was added to asolution of tert-butyl (3R,4S)-4-amino-3-hydroxypiperidine-l-carboxylate (compound 8-a) (500 mg, 2.3 mmol) in DCM (6 mL). 4-Fluoro-2-(trifluoromethyl)benzoyl chloride (compound 2-a) (524 mg, 2.3 mmol) was then added at 25°C and the mixture stirred for 2 hours, concentrated and purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 70 / 30) to afford the title compound (774 mg, 1.9 mmol, 82%) as a colorless oil.

[0107] MS (ESI) m / z = 351 [M+H]+.

[0108] Step 2 : 4-Fluoro-N-((3R, 4S)-3-hydroxypiperidin-4-yl)-2-(trifluoromethyl)benzamide (compound 10). TFA (2.17 g, 19 mmol) was added to a solution of tert-butyl(3R,4S)-4-(4- fluoro-2-(trifluoromethyl)benzamido)-3 -hydroxypiperidine- 1 -carboxylate (compound 9-a) (774 mg, 1.9 mmol) in DCM (8 mL) at 25°C, and the mixture was stirred for 1 hour. Water (20 mL) was added and the pH adjusted to pH 9 by addition of sodium hydroxide solution (1 M). The mixture was extracted with EtOAc (3xl50mL), washed with brine, dried, filtered and concentrated to afford the title compound (479 mg, 1.6 mmol, 82%) as a white solid.

[0109] MS (ESI) m / z = 307 [M+H]+

[0110] Step 3 : N-((3R, 4S)-l-(4-chlorophthalazin-l-yl)-3-hydroxypiperidin-4-yl)-4-fluoro-2- (trifluoromethyl)benzamide (compound 11-a). Potassium carbonate (290 mg, 2.1 mmol) and 4-fluoro-N-((3R,4S)-3-hydroxypiperidin-4-yl) -2-(trifluoromethyl)benzamide (compound 10) (429 mg, 1.4 mmol) were added to a solution of 1,4-di chlorophthalazine (compound 5-a) (307 mg, 1.5 mmol) in NMP (5 mL) and the mixture was stirred at 80°C for 14 hours. After cooling to room temperature, water (50 mL) was added, resulting in the formation of a solid. The mixture was filtered, concentrated, and purified by prep-HPLC (alkaline conditions; Xtimate C18 150x40mmxl0um; water (10mMNH4HCO3)-ACN) to afford the title compound (315 mg, 672 umol, 48%) as a white solid.

[0111] MS (ESI) m / z = 469 [M+H]+

[0112] Step 4 4-Fluoro-N-( 3-hydroxy-l-(4-( 1 -methyl- 1 H-pyrazol-5-yl)phthalazin- 1- yl)piperidin-4-yl)-2-(trifhioromethyl)benzamide (compound M63). Pd(PPhs)4 (86.3 mg, 75 pmol) and N-((3R,4S)-l-(4-chlorophthalazin-l-yl)-3-hydroxypiperidin-4-yl)-4-fluoro-2- (trifluoromethyl)benzamide (compound 11-a) (350 mg, 747 umol) were added to a solution of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (compound 7-a) (544 mg, 2.6 mmol) in toluene (24 mL), ethanol (6 mL), and water (6 mL) and the mixture stirredat 25°C for 20 minutes. Sodium carbonate (119 mg, 1.1 mmol) was added and the mixture was stirred at room temperature for 10 minutes and then heated to 100°C for 12 hours. After cooling to room temperature, water (50mL) was added, resulting in the formation of a solid. The mixture was filtered, concentrated, and purified by prep-HPLC (alkaline conditions; Xtimate C18 150x40mmxl0um; water(10mMNH4HCO3)-ACN) to afford the title compound (210 mg, 406 umol, 54%, 99.4% purity) as a white solid.

[0113] MS (ESI) m / z = 515.3 [M+H]+

[0114] 'HNMR (400 MHz, d6-DMSO) 5 ppm 8.44 - 8.32 (m, 2H), 8.02 - 7.87 (m, 3H), 7.72 - 7.61 (m, 4H), 6.67 (d, J = 1.8 Hz, 1H), 5.23 (d, J = 4.8 Hz, 1H), 4.21 - 4.13 (m, 1H), 4.09 - 4.04 (m, 2H), 4.02 - 3.94 (m, 2H), 3.86 (s, 3H), 3.42 (br d, J = 12.6 Hz, 2H), 2.28 - 2.16 (m, 1H), 1.86 - 1.78 (m, 1H), 1.24 (s, 2H), 1.18 (t, J = 7.2 Hz, 2H).Example 7Synthesis of 4-Fluoro-N-(l-(4-( l-methyl-LH-pyrazol-5-yl)phthalazin-l-yl)piperidin-4- yl)-2-trifluoromethyl)benzamide (Compound M75).

[0115] The synthesis of compound M75 was carried out using the following procedure according to the scheme laid out below.

[0116] Step 1 Tert-butyl 4-(4-fluoro-2-( trifluoromethyl) benzamido)piperidine-l- carboxylate (compound 3-a). TEA (758 mg, 7.5 mmol) was added to a solution of tert-butyl 4- aminopiperidine-1 -carboxylate (compound 1-a) (1.0 g, 5.0 mmol) in DCM (10 mL). 4-Fluoro-2-(trifluoromethyl)benzoyl chloride (compound 2-a) (1.12g, 5.0 mmol) was added at 25°C and the mixture stirred for 2 hours, concentrated, and purified by column chromatography (SiCL, Petroleum ether / Ethyl acetate=100 / l to 70 / 30) to afford the title compound (1.9 g, 4.9 mmol, 97%) as a colorless oil.

[0117] Step 2: 4-fluoro-N-(piperidin-4-yl)-2-(trifluoromethyl)benzamide (compound 4). TFA (5.5 g, 49 mmol) was added to a solution of tert-butyl 4-(4-fluoro-2-(trifluoromethyl) benzamido)piperidine-l -carboxylate (compound 3-a) (1.9 g, 4.9 mmol) in DCM (20 mL) at 25°C, and the mixture was stirred for 1 hour. Water (20 mL) was added and the pH adjusted to pH 9 by addition of sodium hydroxide solution (1 M). The mixture was extracted with EtOAc (3xl50mL), washed with brine, dried, filtered, and concentrated to afford the title compound (1.1 g, 3.9 mmol, 81%) as a white solid.

[0118] MS (ESI) m / z = 291 [M+H]+

[0119] Step 3 N-( 1 -( 4-chlorophthalazin-l-yl)piperidin-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide (compound 6-a). Potassium carbonate (651 mg, 4.7 mmol) and 4- fluoro-N-(piperidin-4-yl)-2-(trifluoromethyl)benzamide (compound 4) (1.1 g, 3.9 mmol) were added to a solution of 1,4-di chlorophthalazine (compound 5-a) (1.9 g, 9.8 mmol) in NMP (10 mL) and the mixture was stirred at 80°C for 14 hours. After cooling the mixture to room temperature, water (60 mL) was added to the mixture, resulting in the formation of a solid. The mixture was filtered, concentrated, and purified by column chromatography (SiCh, Petroleum ether / Ethyl acetate=100 / l to 65 / 35) to afford the title compound (1.1 g, 2.4 mmol, 62%) as a white solid.

[0120] MS (ESI) m / z = 453.1 [M+H]+

[0121] Step 4 : 4-Fluoro-N-( l-(4-(l -methyl- IH-pyr azol-5-yl)phthalazin- 1 -yl)piperidin-4-yl) - 2-trifhioromethyl)benzamide (compound M75). Pd(PPhs)4 (230 mg, 199 umol) and N-(l-(4- chlorophthalazin- 1 -yl)piperidin-4-yl)-4-fluoro-2-(trifluoromethyl)benzamide (compound 6-a) (900 mg, 2.0 mmol) were added to a solution of l-methyl-5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-lH-pyrazole (compound 7-a) (1.4 g, 7.0 mmol) in toluene (36 mL), ethanol (12 mL) and water (12 mL) and the mixture stirred at 25°C for 20 minutes. Sodium carbonate (253 mg, 2.4 mmol) was added and the mixture was stirred for 10 minutes and then heated at 100°C for 12 hours. After cooling to room temperature, the mixture was filtered and the filtrate concentrated to provide a residue which was purified by prep-HPLC (alkaline conditions;Xtimate C18 150x40mmxl0um; water (lOmM NH4HCO3)-ACN. The product was further purified by re-crystallization from n-heptane (50 mL) at 0°C, to afford the title compound (310 mg, 620 umol, 31% yield, 99.7% purity) as a white solid.

[0122] MS (ESI) m / z = 499.2 [M+H]+.

[0123] 'HNMR (400 MHz, d6-DMSO) 5 ppm 8.66 (d, J = 7.6 Hz, 1H), 8.15 (d, J = 8.2 Hz, 1H), 8.05 - 7.90 (m, 3H), 7.73 (d, J = 9.0 Hz, 1H), 7.67 - 7.61 (m, 3H), 6.68 (d, J = 1.8 Hz, 1H), 4.14 - 4.02 (m, 1H), 3.94 (br d, J = 14.0 Hz, 2H), 3.29 - 3.22 (m, 2H), 2.07 (br d, J = 10.2 Hz, 2H), 1.90 - 1.78 (m, 2H)

[0124] It is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and / or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

[0125] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[0126] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimedindividually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and / or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[0127] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of’ excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of’ limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are inherently or expressly described and enabled herein.

[0128] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

Claims

We Claim:

1. A method of treating fibrosis comprising administering a therapeutically effective amount of a compound, wherein the compound is compound M75:M75, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

2. A method of treating fibrosis comprising administering a therapeutically effective amount of a compound, wherein the compound is compound M63:M63, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

3. The method of claim 1 or claim 2, comprising administering between about 25 mg and about 400 mg of the compound.

4. The method of claim 3, comprising administering between about 25 mg / day and about 400 mg / day of the compound.

5. The method of claim 3, comprising administering about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, or about 400 mg of the compound.

6. The method of claim 5, comprising administering about 25 mg / day, about 50 mg / day, about 100 mg / day, about 150 mg / day, about 200 mg / day, about 250 mg / day, about 300mg / day, about 350 mg / day, or about 400 mg / day of the compound.

7. The method of claim 1 or claim 2, wherein an initial dosage of between about 100 mg and about 300 mg is administered, but upon the patient experiencing a drug-related adverse event, the dosage is stepped down.

8. The method of any one of claims 1-7, wherein the fibrosis is idiopathic pulmonary fibrosis.

9. The method of any one of claims 1-8, wherein the fibrosis is pulmonary fibrosis following a pulmonary infection.

10. The method of claim 9, wherein the pulmonary infection is infection by SARS-CoV- 2.

11. The method of any one of claims 1-8, wherein the fibrosis is systemic scleroderma.

12. The method of any one of claims 1-11, wherein the subject does not experience an adverse event of grade 3 or greater.

13. The method of any one of claims 1-12, wherein fibrosis does not progress after initiation of treatment.

14. The method of any one of claims 1-10 or 12-13, wherein the fibrosis is a pulmonary fibrosis and the subject experiences a stabilization of lung function.

15. The method of any one of claims 1-10 or 12-13, wherein the fibrosis is a pulmonary fibrosis and the subject experiences improvement of lung function.

16. The method of any one of claims 1-10 or 12-15, wherein the fibrosis is a pulmonary fibrosis and the subject experiences a decrease in scarring.