Methods for treating fibrotic disease

Abstract

The present disclosure relates to the use of a compound of Formula I to treat an individual with fibrotic disease or at risk of fibrosis.

Description

[0001] METHODS FOR TREATING FIBROTIC DISEASE Background Fibrosis is a pathological condition characterized by the excessive accumulation of extracellular matrix components, leading to scarring and functional impairment of affected tissues. Fibrotic diseases encompass a wide range of disorders affecting various organs, including idiopathic pulmonary fibrosis (IPF), liver fibrosis, chronic kidney disease (CKD), uterine fibrosis, and ovarian fibrosis. Despite their diverse etiologies, these conditions share common pathological mechanisms, including chronic inflammation, activation of fibroblasts, and dysregulated wound healing processes. Current therapeutic options for fibrotic diseases are limited and often focus on managing symptoms rather than targeting the underlying fibrotic process. Therefore, there is an urgent need for novel therapeutic agents that can effectively halt or reverse the progression of fibrosis. Summary In a first aspect, the disclosure provides methods for treating or limiting development of fibrotic diseases, disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of having the chemical formula of Formula I, wherein Formula I is or a pharmaceutically acceptable salt thereof. In one embodiment, the subject has fibrotic disease or is at risk of developing fibrotic disease, and the method serves to treat or limit development of fibrotic disease. In one such embodiment, fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), liver fibrosis, chronic kidney disease (CKD), uterine fibrosis, and ovarian fibrosis. In one embodiment, the subject has IPF, and the method serves to treat IPF, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of reducing pulmonary inflammation, reducing lung scarring, improving progression free survival, improving 6-minute walk distance, improving forced vital capacity (FVC), delaying need for lung transplantation, limiting development of pulmonary hypertension, limiting development of respiratory failure, limiting development of lung cancer, limiting development of right sided heart failure and recovering lost body weight. In one such embodiment, treating limits the development of IPF in a subject at risk of developing IPF, wherein the subject has one or more risk factors of IPF selected from the group consisting of age 70 or older; a family history of IPF; mucin 5B (MUC5B) rs35705950 locus (gain-of-function promoter variant) single nucleotide polymorphism; cigarette smoking; previous infection with one or more of Epstein-Barr virus, Influenza virus, Herpesviruses or Hepatitis C virus; and gastroesophageal reflux disease (GERD). In another embodiment, the subject has liver fibrosis, and the method serves to treat liver fibrosis, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of limiting development of liver cirrhosis, limiting development of liver failure, limiting development of portal hypertension, delaying need for liver transportation, reducing ascites, limiting development of hepatic encephalopathy, limiting development of hepatorenal syndrome, and reducing variceal bleeding. In one such embodiment, treating limits the development of liver fibrosis in a subject at risk of developing liver fibrosis, wherein the subject has one or more risk factors of liver fibrosis selected from the group consisting of autoimmune hepatitis, biliary obstruction, iron overload, nonalcoholic fatty liver disease, Hepatitis B virus, Hepatitis C virus, and long-term excesses of drinking alcohol. In one embodiment, the subject has CKD, and the method serves to treat CKD, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of slowing progression to end-stage renal disease (ESRD), delaying initiation of long-term dialysis, delaying need for kidney transplantation, increasing estimated glomerular filtration rate (eGFR), reducing urine albumin-creatine ratio (UACR) and normalizing proteinuria. In one such embodiment, treating limits the development of CKD in a subject at risk of developing CKD, wherein the subject has one or more risk factors of CKD selected from the group consisting of age 60 or older, diabetes, heart disease, a family history of CKD or renal failure, inherited kidney disorders, past damage to kidneys and smoking or tobacco use. In another embodiment, the subject has uterine fibrosis, and the method serves to treat uterine fibrosis, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of delaying need for surgical intervention, reducing fibroid volume, and reducing menstrual bleeding. In one such embodiment, treating limits the development of uterine fibrosis in a subject at risk of developing uterine fibrosis, wherein the subject has one or more risk factors for uterine fibrosis selected from the group consisting of age 40 or older, premenopausal state, family history of uterine fibroids, hypertension, frequent consumption of soybean milk and parity. In a further embodiment, the subject has ovarian fibrosis, and the method serves to treat ovarian fibrosis, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of reducing ovarian chocolate cyst formation, limiting development of polycystic ovarian syndrome (PCOS), limiting premature ovarian failure, and limiting development of ovarian cancer. In one such embodiment, treating limits the development of ovarian fibrosis, wherein the subject one or more risk factors for ovarian fibrosis selected from the group consisting of previous history of surgery, inflammation, and immune abnormalities. In another embodiment, the method serves to treat or limit the development of one or more of pulmonary inflammation, lung scarring, pulmonary hypertension, respiratory failure, ESRD, ovarian chocolate cysts, PCOS, ovarian failure, ovarian cancer, cirrhosis, liver failure, portal hypertension, ascites, hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding comprising administering to a subject in need thereof a therapeutically effective amount of ABI-171. Description of Figures Figure 1. Preventative IPF treatment study using animal model: (A) Scheme showing bleomycin (BLM) animal model; (B) Graph showing body weight changes over time in control, vehicle treated (BLM), pirfenidone (100 mg / kg, twice daily (TD), oral), ABI-154 (60 mg / kg, daily (QD), intranasal (IN)), and ABI-171 (60 mg / kg, QD, IN). Note body weight loss induced by bleomycin while ABI-171 group showed significant increase in body weight from Day 14 to 21 and an improved delta body weight compared to the model group; (C) Graph showing collagen content in the lung tissue for the previously mentioned groups assessed by the hydroxyproline content; (D) Graphs showing lymphocyte and (E) neutrophil cell counts in previously mentioned groups. Significant increase in the BLM group and significant reduction in the ABI-171 group indicating a potent anti-inflammatory effect; (F) Graphs showing left lung H&E staining score to determine fibrosis and (G) left lung Masson’s trichrome staining to determine collagen deposition in previously mentioned groups. Alveolar septa thickening, as well as collagen deposition was observed in the BLM group. Whereas groups treated with ABI-154 and ABI-171 had a gradual decrease in the alveolitis and pulmonary fibrosis degree relative to the BLM group; (H) Representative histological staining for previously mentioned groups with arrows indicating fibrosis with lung tissue destruction. Figure 2. Therapeutic IPF treatment study using animal model: (A) Scheme showing BLM animal model with ABI-171 and EGCG treatments; (B) Graph showing Kaplan-Meier survival curve analysis for control, BLM treated with vehicle, pirfenidone (100mg / kg, TD, oral), epigallocatechin gallate(EGCG) (100mg / kg, QD, oral), ABI-171 (100mg / kg, QD, oral), ABI-171 (10mg / kg, QD, IN), and ABI-171 (50mg / kg, QD, IN). Treatment with EGCG resulted in significantly lower survival rate (50% mortality), while oral and 50mg / kg intranasal doses of ABI-171 resulted in complete survival and 10mg / kg intranasal ABI-171 resulted in 67% survival; (C) Graph showing body weight changes in (G1) control, (G2)BLM treated with vehicle, (G3) pirfenidone (100mg / kg, TD, oral), (G4) Epigallocatechin Gallate(EGCG) (100mg / kg, QD, oral), (G5) ABI-171 (100mg / kg, QD, oral), (G6) ABI-171 (10mg / kg, QD, IN), and (G7) ABI-171 (50mg / kg, QD, IN). In G5, where ABI-171 was administered orally, there’s recovery in animal body weight; (D) Graph showing lymphocyte cell counts in previously mentioned group; (E) Graphs showing H&E staining score and (F) Masson’s trichrome staining score to determine lung injury severity. ABI-171 ameliorated the severity of BLM-induced lung injuries; (G) Representative histological pictures for the previously mentioned groups with arrows indicating fibrosis with lung structural destruction; (H) Graph showing fibronectin analysis for the previously mentioned groups; (I) Graph showing collagen I analysis for the previously mentioned groups; J) Graph showing E- Cadherin analysis for the previously mentioned groups; K) Graph showing IL-6 analysis for the previously mentioned groups; L) Graph showing PIM1 analysis for the previously mentioned groups; M) Graph showing -SMA analysis for the previously mentioned groups; N) Graph showing pSMAd3 analysis for the previously mentioned groups; O) Graph showing Snail analysis for the previously mentioned groups (* P<0.05, ** P<0.01; *** P<0.001; VS. G2, Unpaired t-test). Figure 3: General antifibrotic activity of ABI-171using the STAM / NASH (nonalcoholic steatohepatitis) mouse model. (A) Graph showing quantifications of percent area of collagen deposition, as shown by Sirius red staining of fixed liver sections, from untreated (Normal), PEG400(SMC + vehicle), and ABI-171 treated (SMC + ABI-171; 100mg / kg, OS, QD, 4 weeks treatment between the age of 6 to 10 weeks old) mice. (B) Representative histological pictures for the previously mentioned groups. Figure 4: Antifibrotic activity of ABI-171 in the methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) mouse model. (A) Graph showing quantification of percent area of collagen deposition, as assessed by Masson staining of fixed liver sections, from normal diet + vehicle (G1), MCD diet + vehicle (G2), MCD diet + EGCG (50 mg / kg, oral, daily, G3), and MCD diet + ABI-171 (50 mg / kg, oral, daily, G4) groups. ABI-171 treatment (G4) significantly reduced collagen deposition compared to the MCD + vehicle group (G2) (****P<0.0001, one-way ANOVA, N=6). (B) Representative histological images of liver sections stained with Masson’s trichrome for the aforementioned groups, with staining indicating collagen deposition. (C) Graph showing serum free fatty acid (FFA) levels, with ABI-171 (G4) demonstrating a significant reduction (**P<0.01) compared to G2, and a stronger effect than EGCG (G3, *P<0.05). (D) Hematoxylin and Eosin (H&E) staining scores for steatosis, lobular inflammation, and hepatocellular ballooning, showing significant reductions in G4 (***P<0.001, ****P<0.0001 vs. G2). Detailed description As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. “And” as used herein is interchangeably used with “or” unless expressly stated otherwise. Terms used herein may be preceded and / or followed by a single dash, “-”, or a double dash, “=“, to indicate the bond order of the bond between the named substituent and its parent moiety; a single dash indicates a single bond and a double dash indicates a double bond. In the absence of a single or double dash it is understood that a single bond is formed between the substituent and its parent moiety; further, substituents are intended to be read “left to right” (i.e., the attachment is via the last portion of the name) unless a dash indicates otherwise. For example, C1-C6alkoxycarbonyloxy and -OC(O)C1-C6alkyl indicate the same functionality; similarly, arylalkyl and –alkylaryl indicate the same functionality. The term “alkenyl” as used herein, means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl. The term “alkoxy” as used herein, means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy. The term “alkyl” as used herein, means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2- dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. When an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH2-, -CH2CH2-, -CH2CH2CHC(CH3)-, and-CH2CH(CH2CH3)CH2-. The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, i.e., -(CH2)n-, wherein n is a positive integer, preferably from one to six, from one to four, from one to three, from one to two, or from two to three. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms is replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. An alkylene chain also may be substituted at one or more positions with an aliphatic group or a substituted aliphatic group. The term “alkynyl” as used herein, means a straight or branched chain hydrocarbon group containing from 2 to 10 carbon atoms and containing at least one carbon-carbon triple bond. Representative examples of alkynyl include, but are not limited, to acetylenyl, 1- propynyl, 2-propynyl, 3-butynyl, 2-pentynyl, and 1-butynyl. The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or a phenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or a monocyclic heterocyclyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the phenyl portion of the bicyclic system, or any carbon atom with the napthyl or azulenyl ring. The fused monocyclic cycloalkyl or monocyclic heterocyclyl portions of the bicyclic aryl are optionally substituted with one or two oxo and / or thia groups. Representative examples of the bicyclic aryls include, but are not limited to, azulenyl, naphthyl, dihydroinden-1-yl, dihydroinden-2-yl, dihydroinden-3-yl, dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl, 2,3-dihydroindol-6-yl, 2,3- dihydroindol-7-yl, inden-1-yl, inden-2-yl, inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl, dihydronaphthalen-4-yl, dihydronaphthalen-1-yl, 5,6,7,8- tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl, 2,3-dihydrobenzofuran-4-yl, 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl, 2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl, benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2- on-6-yl, 2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl, isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl, inden-1-on-6-yl, inden-1-on-7- yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl, 2,3-dihydrobenzo[b][1,4]dioxan-6-yl, 2H- benzo[b][1,4]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-6-yl, 2H- benzo[b][1,4]oxazin3(4H)-on-7-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-8-yl, benzo[d]oxazin- 2(3H)-on-5-yl, benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl, benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl, quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl, quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl, quinoxalin- 2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl, quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)- on-4-yl, benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and, benzo[d]thiazol- 2(3H)-on-7-yl. In certain embodiments, the bicyclic aryl is (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5 or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. The terms “cyano” and “nitrile” as used herein, mean a -CN group. The term “cycloalkyl” as used herein, means a monocyclic or a bicyclic cycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings. Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2)w-, where w is 1, 2, or 3). Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring. Cycloalkyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a 5 or 6 membered monocyclic cycloalkyl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused bicyclic cycloalkyl is optionally substituted by one or two groups which are independently oxo or thia. The term “halo” or “halogen” as used herein, means -Cl, -Br, -I or -F. The terms "haloalkyl" and "haloalkoxy" refer to an alkyl or alkoxy group, as the case may be, which is substituted with one or more halogen atoms. The term “heteroaryl,” as used herein, means a monocyclic heteroaryl or a bicyclic ring system containing at least one heteroaromatic ring. The monocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ring consists of two double bonds and one, two, three or four nitrogen atoms and optionally one oxygen or sulfur atom. The 6 membered ring consists of three double bonds and one, two, three or four nitrogen atoms. The 5 or 6 membered heteroaryl is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heteroaryl. Representative examples of monocyclic heteroaryl include, but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclic heteroaryl group is optionally substituted with one or two groups which are independently oxo or thia. When the bicyclic heteroaryl contains a fused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon or nitrogen atom contained within the monocyclic heteroaryl portion of the bicyclic ring system. When the bicyclic heteroaryl is a monocyclic heteroaryl fused to a benzo ring, then the bicyclic heteroaryl group is connected to the parent molecular moiety through any carbon atom or nitrogen atom within the bicyclic ring system. Representative examples of bicyclic heteroaryl include, but are not limited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl, benzoxathiadiazolyl, benzothiazolyl, cinnolinyl, 5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl, indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl, 5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl, 5,6,7,8- tetrahydroquinolin-4-yl, 5,6,7,8-tetrahydroisoquinolin-1-yl, thienopyridinyl, 4,5,6,7- tetrahydrobenzo[c][1,2,5]oxadiazolyl, 2,3-dihydrothieno[3,4-b][1,4]dioxan-5-yl, and 6,7- dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments, the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroaryl ring fused to either a phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. The terms “heterocyclyl” and “heterocycloalkyl” as used herein, mean a monocyclic heterocycle or a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6, 7, or 8 membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S where the ring is saturated or unsaturated, but not aromatic. The 3 or 4 membered ring contains 1 heteroatom selected from the group consisting of O, N and S. The 5 membered ring can contain zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The 6 or 7 membered ring contains zero, one or two double bonds and one, two or three heteroatoms selected from the group consisting of O, N and S. The monocyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle. Representative examples of monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a bridged monocyclic ring or a monocyclic heterocycle fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclic heteroaryl. Bridged monocyclic rings contain a monocyclic heterocycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH2)w-, where w is 1, 2, or 3). The bicyclic heterocycle is connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the monocyclic heterocycle portion of the bicyclic ring system. Representative examples of bicyclic heterocyclyls include, but are not limited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofuran-3-yl, indolin-1-yl, indolin-2-yl, indolin- 3-yl, 2,3-dihydrobenzothien-2-yl, decahydroquinolinyl, decahydroisoquinolinyl, octahydro- 1H-indolyl, and octahydrobenzofuranyl. Heterocyclyl groups are optionally substituted with one or two groups which are independently oxo or thia. In certain embodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclic heterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl, wherein the bicyclic heterocyclyl is optionally substituted by one or two groups which are independently oxo or thia. The term “oxo” as used herein means a =O group. The term “saturated” as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds. For example, a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like. The term "substituted", as used herein, means that a hydrogen radical of the designated moiety is replaced with the radical of a specified substituent, provided that the substitution results in a stable or chemically feasible compound. The term "substitutable", when used in reference to a designated atom, means that attached to the atom is a hydrogen radical, which can be replaced with the radical of a suitable substituent. The phrase "one or more” substituents, as used herein, refers to a number of substituents that equals from one to the maximum number of substituents possible based on the number of available bonding sites, provided that the above conditions of stability and chemical feasibility are met. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and the substituents may be either the same or different. As used herein, the term "independently selected" means that the same or different values may be selected for multiple instances of a given variable in a single compound. The term “thia” as used herein means a =S group. The term “unsaturated” as used herein means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic. For example, an unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like. ABI 171 is: (2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro- 3,4-dihydroxy-5-methoxybenzoate. Referred to as ABI-171 hereafter. ABI 154 is: (2S,3R)- 5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6-difluoro-3,4,5- trihydroxybenzoate. Referred to as ABI-154 hereafter. . (ABI-154) (ABI-171) It will be apparent to one skilled in the art that certain compounds of this disclosure may exist in tautomeric forms, all such tautomeric forms of the compounds being within the scope of the disclosure. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the disclosure. Both the R and the S stereochemical isomers, as well as all mixtures thereof, are included within the scope of the disclosure. All embodiments of any aspect of the disclosure can be used in combination unless the context clearly dictates otherwise. Unless the context clearly requires otherwise, throughout the description and the claims, the words ‘comprise’, ‘comprising’, and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of “including, but not limited to”. Words using the singular or plural number also include the plural and singular number, respectively. Additionally, the words “herein,” “above,” and “below” and words of similar import, when used in this application, shall refer to this application as a whole and not to any particular portions of the application. The compositions and methods for their use can “comprise,” “consist essentially of,” or “consist of” any of the ingredients or steps disclosed throughout the specification. The description of embodiments of the disclosure is not intended to be exhaustive or to limit the disclosure to the precise form disclosed. While the specific embodiments of, and examples for, the disclosure are described herein for illustrative purposes, various equivalent modifications are possible within the scope of the disclosure, as those skilled in the relevant art will recognize. In one aspect, the disclosure provides methods of treating or limiting development of a fibrotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I: R1, R2, R3, and R4are each independently hydrogen, halogen, -NO2, -CN, C1-C10 alkyl, C1-C10 haloalkyl, -NH2, -NH(C1-C10 alkyl), -N(C1-C10 alkyl)2, -OH, C1-C10 alkoxy, C1-C10haloalkoxy, -SH, hydroxy(C1-C10alkyl), alkoxy(C1-C10alkyl),amino(C1-C10alkyl), -CONH2, -CONH(C1-C10alkyl), -CON(C1-C10alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C10alkyl), -OC(O)N(C1-C10alkyl)2, -CO2H, -CO2(C1-C10alkyl), -CHO, -CO(C1-C10alkyl), -OC(O)(C1-C10alkyl), -S(O)0-2(C1- C10alkyl), or -NH(S(O)0-2(C1-C10alkyl)); R5and R9are each independently hydrogen, halogen, -NO2, -CN, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -OH, C1-C6alkoxy, C1-C6haloalkoxy, or -SH; R7is hydrogen, halogen, -NO2, -CN, C1-C10 alkyl, C1-C10 haloalkyl, -NH2, -NH(C1- C10 alkyl), -N(C1-C10 alkyl)2, -OH, C1-C10 alkoxy, C1-C10 haloalkoxy, -SH, hydroxy(C1-C10 alkyl), alkoxy(C1-C10 alkyl), amino(C1-C10 alkyl), -CONH2, -CONH(C1-C10 alkyl), -CON(C1-C10 alkyl)2, -CO2H, -CO2(C1-C10 alkyl), -CHO, -CO(C1-C10 alkyl), -S(O)0-2(C1-C10 alkyl), or -NH(S(O)0-2(C1-C10 alkyl)); R6and R8are each independently hydrogen, halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or -SH; X is O or C; Y is O or NH; and R10and R14are each independently hydrogen, halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or -SH; R12is hydrogen, halogen, -NO2, -CN, C1-C10 alkyl, C1-C10 haloalkyl, -NH2, -NH(C1-C10 alkyl), -N(C1-C10 alkyl)2, -OH, C1-C10 alkoxy, C1- C10haloalkoxy, -SH, hydroxy(C1-C10alkyl), alkoxy(C1-C10alkyl), amino(C1-C10alkyl), -CONH2, -OC(O)NH(C1-C10alkyl), -CON(C1- C10alkyl)2, -CO2H, -CO2(C1-C10alkyl), -CHO, -OC(O)(C1-C10alkyl), -S(O)0-2(C1-C10alkyl), or -NH(S(O)0-2(C1-C10alkyl)); R11and R13are each independently hydrogen, halogen, -NO2, -CN, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -OH, C1-C6alkoxy, C1-C6haloalkoxy, -SH, OC(O)(C1-C10alkyl), or -OC(O)NH(C1-C10 alkyl); or Z n is 0–4; and each R15is independently C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -OH, C1-C6alkoxy, or C1-C6haloalkoxy; R17is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. The methods disclosed herein show anti-fibrotic activity in animal models of fibrotic disease, showing a significant reduction in the deposition of extracellular matrix components and attenuation of fibrotic markers. The methods can thus be used for the treatment and prevention of fibrotic diseases, including but not limited to idiopathic pulmonary fibrosis (IPF), liver fibrosis, chronic kidney disease (CKD), uterine fibrosis, and ovarian fibrosis. As used herein, "treat" or "treating" means accomplishing one or more of the following in an individual that has the recited disorder: (a) reducing the severity of the disorder; (b) slowing the progression of the disorder; (c) inhibiting development of symptoms characteristic of progression of the disorder; or (d) inhibiting worsening of symptoms characteristic of the disorder(s) being treated. Any amount of such “treating” is of great benefit to a subject one of the recited disorders. As used herein, "limit" or "limiting development of" means accomplishing one or more of the following in an individual that is at risk of the recited disorder: (a) slowing progression to onset of the disorder (b) limiting or preventing development of symptoms characteristic of the disorder being limited; (c) recurrence of the disorder in patients that have previously had the disorder; or (d) limiting or preventing recurrence of symptoms in patients that were previously symptomatic for the disorder. Any amount of such “limiting development” is of great benefit to a subject at risk of one of the recited disorders. In one embodiment, the subject has IPF, and the method serves to treat the IPF. As shown in the examples that follow, the disclosed compounds improved survival, recovered body weight, reduced lung inflammation, fibrosis, and alveolar tissue damage in a therapeutic treatment study using the bleomycin mouse model of IPF. Thus, the method of this embodiment can be used to treat IPF. Such symptoms of IPF include but are not limited to: pulmonary inflammation, lung scarring, pulmonary hypertension, lung cancer, respiratory failure, right-sided heart failure, chest pain or tightness, leg swelling, loss of appetite, tiredness, joint and muscle aches, unexplained weight loss, clubbing (widening of the tips of fingers and toes), dyspnea (shortness of breath) dry cough, need for lung transplantation, and death due to IPF complications. As will be understood by those of skill in the art, any benefits and / or reducing symptoms of IPF provides a great benefit to the subject with IPF. Thus, in some embodiments, the treating may comprise reducing pulmonary inflammation, reducing lung scarring, improving progression free survival, improving 6- minute walk distance, improving forced vital capacity (FVC), delaying need for lung transplantation, limiting development of pulmonary hypertension, limiting development of respiratory failure, limiting development of right sided heart failure, and recovering lost body weight. In another embodiment, the subject is at risk of IPF, and the method serves to limit the development of IPF in the subject. As shown in the examples that follow, the disclosed compounds limited body weight loss, limited lung inflammation, fibrosis, and alveolar tissue damage in a preventative treatment study using the bleomycin mouse model of IPF. In this embodiment, the subject at risk for IPF has one or more risk factor for IPF. Such risk factors for IPF include, but are not limited to, being age 70 or older, a family history of IPF, variants of the MUC5B gene, cigarette smoking, previous infection with one or more of Epstein-Barr virus, Influenza virus, Herpesviruses or Hepatitis C virus, and gastroesophageal reflux disease (GERD). As will be understood by those of skill in the art, any limit on the development of IPF or its symptoms provides great benefit to a subject at risk of developing IPF. In one embodiment, the subject has liver fibrosis, and the method serves to treat liver fibrosis. As shown in the examples that follow, the disclosed compounds reduced liver fibrosis in a STAM mouse model of NASH (nonalcoholic steatohepatitis). Thus, the method of this embodiment can be used to treat liver fibrosis. Symptoms of liver fibrosis include, but are not limited to, unexplained fatigue, unexplained nausea or vomiting, loss of appetite, unexplained weight loss, discomfort in the upper-right of the abdomen, bleeding or bruising easily, unexplained confusion, memory issues, difficulty sleeping, swelling in the lower extremities from edema, severe itching, dark- colored urine, jaundice, and portal hypertension. As will be understood by those of skill in the art, any benefits and / or reducing symptoms of liver fibrosis provides a great benefit to the subject with ovarian fibrosis. In some embodiments, the treating may comprise reducing cirrhosis, delaying liver failure, reducing portal hypertension, delaying need for liver transplantation, reducing ascites, limiting development of hepatic encephalopathy, limiting development of hepatorenal syndrome, and reducing variceal bleeding. In another embodiment, the subject is at risk of liver fibrosis, and the method serves to limit the development of liver fibrosis in the subject. In this embodiment, the subject at risk of liver fibrosis has one or more risk factors for liver fibrosis. Such risk factors for liver fibrosis include, but are not limited to, autoimmune hepatitis, biliary obstruction, iron overload, nonalcoholic fatty liver disease, Hepatitis B virus, Hepatitis C virus, and long-term excess of drinking alcohol. As will be understood by those of skill in the art, any limit on the development of liver fibrosis or its symptoms provides great benefit to a subject at risk of developing liver fibrosis. In one embodiment, the subject has CKD, and the method serves to treat the CKD. Symptoms of CKD include, but are not limited to, weight loss, poor appetite, swollen ankles, feet, or hands due to water retention; shortness of breath, tiredness, increased nighttime need to urinate, insomnia, itchy skin, muscle cramps, headaches, and erectile dysfunction. As will be understood by those of skill in the art, any benefit and / or reducing the symptoms of CKD provides a great benefit to the subject with CKD. In some embodiments, the treating may comprise slowing progression to end-stage renal disease (ESRD), delaying initiation of long-term dialysis, delaying need for kidney transplantation, increasing estimated glomerular filtration rate (eGFR), reducing urine albumin-creatine ratio (UACR) and normalizing proteinuria. In another embodiment, the subject is at risk of CKD, and the method serves to limit the development of CKD in the subject. As shown in the examples that follow, the disclosed compounds. In this embodiment, the subject at risk of CKD has one or more risk factors for CKD. Such risk factors for CKD include, but are not limited to, being age 60 or older, a family history of CKD or renal failure, inherited kidney disorders, past kidney damage, smoking or tobacco use, diabetes, heart disease, and obesity. As will be understood by those of skill in the art, any limit on the development of CKD or its symptoms provides great benefit to a subject at risk of developing CKD. In one embodiment, the subject has uterine fibrosis, and the method serves to treat uterine fibrosis. Symptoms of uterine fibrosis include, but are not limited to, constipation, intermenstrual periods, frequent urination, heavy menstrual bleeding, lengthy periods, leg pain, lower back pain, pain during intercourse, pelvic pain, rectal pain, and infertility. As will be understood by those of skill in the art, any benefits and / or reducing symptoms of uterine fibrosis provides a great benefit to the subject with uterine fibrosis. In some embodiments, the treating may comprise delaying need for surgical intervention, reducing menstrual bleeding, and reducing fibroid volume. In another embodiment, the subject is at risk of uterine fibrosis, and the method serves to limit the development of uterine fibrosis in the subject. In this embodiment, the subject at risk of uterine fibrosis has one or more risk factors for uterine fibrosis. Such risk factors for uterine fibrosis include, but are not limited to, being 40 years or older, premenopausal state, a family history of uterine fibroids, hypertension, frequent consumption of soybean milk, and parity (number of births). As will be understood by those of skill in the art, any limit on the development of uterine fibrosis or its symptoms provides great benefit to a subject at risk of developing uterine fibrosis. In one embodiment, the subject has ovarian fibrosis, and the method serves to treat ovarian fibrosis. Symptoms of ovarian fibrosis include, but are not limited to, abnormal menstruation, hirsutism, acne, obesity, acanthosis nigricans, egg sac cysts, skin tags, thinning hair, and infertility. As will be understood by those of skill in the art, any benefits and / or reducing symptoms of ovarian fibrosis provides a great benefit to the subject with ovarian fibrosis. In some embodiments, the treating may comprise reducing ovarian chocolate cyst formation, limiting development of polycystic ovarian syndrome (PCOS), delaying premature ovarian failure, and limiting development of ovarian cancer. In another embodiment, the subject is at risk of ovarian fibrosis, and the method serves to limit the development of ovarian fibrosis in the subject. In this embodiment, the subject at risk of ovarian fibrosis has one or more risk factors for ovarian fibrosis. Such risk factors for ovarian fibrosis include, but are not limited to, previous surgery, inflammation, and immune abnormalities. As will be understood by those of skill in the art, any limit on the development of ovarian fibrosis or its symptoms provides great benefit to a subject at risk of developing ovarian fibrosis. In another aspect, the disclosure provides methods for treating or limiting development of one or more of pulmonary inflammation, lung scarring, pulmonary hypertension, respiratory failure, ESRD, ovarian chocolate cysts, PCOS, ovarian failure, ovarian cancer, cirrhosis, liver failure, portal hypertension, ascites, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding, comprising administering to a subject with one or more of the disorders an amount effective of a compound of Formula I to treat or limit development of the disorder. As used herein in all aspects, a “therapeutically effective amount” or an “effective amount” refers to an amount of the composition that is effective for treating and / or limiting the relevant disorder. Amounts effective for these uses depend on factors including, but not limited to, the specific compound, the route of administration, the stage and severity of the disorder, the weight and general state of health of the subject, and the judgment of the prescribing physician. It will be understood that the amount of the composition actually administered will be determined by a physician, in the light of the above relevant circumstances. In one non-limiting embodiment, an amount effective is an amount that provides between 0.01 mg / kg to about 50 mg / kg of body weight per day. The subject may be any subject with or at risk of fibrotic diseases, including mammals, humans, cattle, dogs, cats, horses, chickens, and so on. In one embodiment, the subject is human. The compounds may be the sole active agent, or they may be combined with one or more other therapeutic and / or prophylactic agents as deemed appropriate by attending medical personnel. In one embodiment, treating IPF may comprise use of the compounds in combination with one or more of pirfenidone, nintedanib, or pharmaceutically acceptable salts thereof. Side effects associated with pirfenidone use include gastrointestinal (nausea, dyspepsia, vomiting, and anorexia), skin-related (rash and photosensitivity), and neurologic (headache and dizziness) symptoms; fatigue; and elevated hepatic enzyme levels. Diarrhea is associated with nintedanib use. The methods of this embodiment can, for example, permit use of lower doses of pirfenidone, nintedanib, or pharmaceutically acceptable salts thereof, and thus mitigate their recited side effects. In another embodiment, treating CKD may comprise use of the compounds in combination with angiotensin-converting enzyme (ACE) inhibitors including ramipril, enalapril, or pharmaceutically acceptable salts thereof. Side effects associated with ACE inhibitor use include persistent dry cough, dizziness, tiredness, weakness, and headaches. The methods of this embodiment can, for example permit use of lower doses of ACE inhibitors or pharmaceutically acceptable salts thereof, and thus mitigate their recited side effects. In one embodiment, treating uterine fibrosis may comprise use of the compounds in combination with gonadotropin releasing hormone (GnRH) agonists including leuprolide and triptorelin or pharmaceutically acceptable salts thereof. Side effects associated with GnRH agonist use include hot flashes, breast tenderness or pain, vaginal discharge, dryness or itching; spotting, decrease in sexual ability or desire, swelling of hands, feet, ankles or lower legs; pain, burning or tingling in the hands or feet; change of weight, muscle or joint pain, runny nose, cough, sore throat, flu-like symptoms, fever, stomach pain, constipation, headache, acne, depression, uncontrolled emotions, frequent mood changes, nervousness, and memory difficulty. The methods of this embodiment can, for example permit use of lower doses of GnRH agonists or pharmaceutically acceptable salts thereof, and thus mitigate their recited side effects. In another embodiment, treating ovarian fibrosis may comprise use of the compounds in combination with hormonal contraceptives or pharmaceutically acceptable salts thereof. Side effects associated with hormonal contraceptive use include nausea, headaches, abdominal cramping, breast tenderness, increased vaginal discharge, and decreased libido. The methods of this embodiment can, for example permit use of lower doses of hormonal contraceptives or pharmaceutically acceptable salts thereof, and thus mitigate their recited side effects. In one embodiment, treating liver fibrosis may comprise use of the compounds in combination with angiotensin-converting enzyme (ACE) inhibitors including ramipril, enalapril, or pharmaceutically acceptable salts thereof. Additionally, resmetirom, a thyroidhormone receptor- agonist that helps reduce liver fat and inflammation but lacks directantifibrotic activity, can be included in the treatment regimen. Side effects associated with ACE inhibitor use include persistent dry cough, dizziness, tiredness, weakness, and headaches. The methods of this embodiment can, for example, permit use of lower doses of ACE inhibitors or pharmaceutically acceptable salts thereof, and thus mitigate their recited side effects. The compounds may be administered via any suitable route, including but not limited to orally, pulmonary, intraperitoneally, via subcutaneous injection, intramuscular injection, or by inhalation or intranasally. In one embodiment, the compounds are administered by inhalation or intranasally. In these embodiments, the compounds may be administered in pharmaceutical composition comprising a permeation enhancer, present in an amount of 1–20wt.%. Examples of suitable permeation enhancers include HP- -CD, glycerin, and chitosan,transmucosal delivery enhancement agents including but not limited to alkylsaccharide transmucosal delivery enhancement agents (including but not limited to tetradecyl maltoside (TDM)), or combinations thereof. In various embodiments the permeation enhancercomprises HP- -CD (such as at a concentration of from about 1.0% to about 20% w / w or anyof the alternative embodiments listed for permeation enhancers in general), chitosan (such as at a concentration of from about 0.1% to about 2% w / w or any of the relevant alternative embodiments listed for permeation enhancers in general), glycerin (such as at a concentration of from about 1% to about 10% w / w or any of the relevant alternative embodiments listed for permeation enhancers in general), PEG 300 (such as at a concentration of from about 1% to about 20% w / w or any of the relevant alternative embodiments listed for permeation enhancers in general), PEG 400 (such as at a concentration of from about 1% to about 20% w / w or any of the relevant alternative embodiments listed for permeation enhancers in general), PEG 600 (such as at a concentration of from about 1% to about 20% w / w or any of the relevant alternative embodiments listed for permeation enhancers in general), and / or transmucosal delivery enhancement agents including but not limited to alkylsaccharide, including but not limited to tetradecyl maltoside (TDM) (such as at a concentration of from about 0.1% to about 2% w / w or any of the relevant alternative embodiments listed for permeation enhancers in general). In certain embodiments as otherwise described herein, the permeation enhancer is present in an amount of 1–20%, e.g., 1-18%, 2-18%, 3-17%, 4-16%, 5-15%, 6-14%, 7-13%, 8-12%, 9-11%, 2.3-10%, or 0.1% to 2% w / w. In certain such embodiments, the permeation enhancer comprises one or more compounds selected from cyclodextrin or analogs thereof, glycerin, PEG 400, sucrose monolaurate, chitosan, transmucosal delivery enhancement agents including but not limited to alkylsaccharide transmucosal delivery enhancement agents (including but not limited to tetradecyl maltoside (TDM)), pharmaceutically acceptable salts thereof, and any combination thereof. In certain such embodiments, the permeation enhancer comprises one or more compounds selectedfrom (2-Hydroxypropyl)- -cyclodextrin (HP- -cyclodextrin); also referred to as HP- -CD,or Hydroxypropyl betadex), randomly methylated cyclodextrin (also referred to as RM- -CD), sulfobutylether- -cyclodextrin (also referred to as SBE- -CD), sucrose monolaurate,pharmaceutically acceptable salts thereof, and any combination thereof. In certain embodiments, the composition for intranasal of inhalation delivery includes an anti-oxidant / chelator, present in an amount of 0.1–20 wt.%. In certain such embodiments, the anti-oxidant / chelator is present in an amount of 0.05-15%, 0.8-15%, 0.1-15%, 0.1-10%, 0.1-9%, or 0.1-6% w / w. In certain such embodiments, the anti-oxidant comprises one or more compounds selected from ascorbic acid, sodium metabisulfite, sodium bisulfite, tocopherol, and pharmaceutically acceptable salts thereof. In another embodiment, the anti- oxidant comprises ascorbic acid, sodium metabisulfite, sodium bisulfite or tocopherol, or metal chelators such as ethylenedaminetetraacetic acid (EDTA), or a pharmaceutically acceptable salt thereof. In certain embodiments as otherwise described herein, the composition for intranasal or inhalation delivery includes a humectant, present in an amount of 1–30 wt.% to increase solubility of the one or more compounds. In certain such embodiments, the humectant is present in an amount of 1-25%, 1-20%, 1-15%, 1-10%, 1-9%, 2-8%, 3-7%, or 4-6% w / w. In certain such embodiments, the humectant comprises one or more compounds selected from glycerin, PEG (including but not limited to PEG 300, PEG400, and PEG 600), pharmaceutically acceptable salts thereof, and any combination thereof. In certain embodiments as otherwise described herein, the composition for intranasal of inhalation delivery includes a preservative, present in an amount of 0.03–2 wt.%, to extend the shelf-life of the composition. In certain such embodiments, the preservative is present in an amount of 0.03–2%, e.g., 0.03–1%, or 0.03–0.5%, or 0.03–0.1 wt.%. In certain such embodiments, the preservative comprises one or more compounds selected from benzyl alcohol, parabens, thimerosal, chlorobutanol and benzalkonium chloride, and any combination thereof. In certain embodiments as otherwise described herein, the composition for intranasal or inhalation delivery includes a pH modifier such as, for example, a citrate, lactate, sodium hydroxide, or phosphate buffer, to make the pH of the intranasal composition physiological and non-irritating. In certain embodiments as otherwise described herein, the composition comprises a pH modifier, present in an amount of 0.1–2% (e.g., 0.5–1.5%) w / w. In certain such embodiments, the pH modifier is sodium hydroxide or a pharmaceutically acceptable salt thereof. The composition for intranasal or inhalation delivery can also include one or more osmogens (e.g., sodium chloride, mannitol, glucose), e.g., to provide an isotonic formulation. An osmolarity of 300–700 mOsmol / kg can desirably increase the viscosity and, accordingly, increase the residence time and improve absorption of the one or more compounds or pharmaceutically acceptable salts thereof (i.e., as otherwise described herein). The intranasal or inhalation pharmaceutical composition may comprise any suitable form for administration. In certain embodiments as otherwise described herein, the composition for administration is in the form of a liquid, a powder, a spray, a nose drop, a gel, an ointment, a nebulizer, a dry powder, or any combination thereof. The composition can be formulated, for example, as an emulsion, ointment, gel, (which offer advantages for local application because of their viscosity) or can be, for example powder formulations or nasal sprays. Such sprays typically comprise a solution of the active drug in physiological saline or other pharmaceutically suitable carrier liquids. Various nasal spray compression pumps can be used and calibrated to deliver a predetermined dose of the one or more compounds of Formula I or a pharmaceutically acceptable salt thereof (i.e., as otherwise described herein). For example, the formulations may be capable of delivering a dose of between about 1 mg to about 100 mg of the active compound, or between about 5 mg to 20 mgs per shot (for example, per pump of a nasal spray) which can be given as one or more shots per nostril. For solution formulations typical volumes used to deliver between about 1 mg to about 100 mg, or between about 5 mg to 20 mgs in man are 25 to 200 μL, or 75 to 150 μL per dose in each nostril. The intranasal solution formulations can be administered as drops from a nasal dropper bottle or as aerosols after being applied from squeeze bottles, single unit dose or metered-dose pump sprays. The dose of a compound for delivery can be combined with a mucoadhesive to enhance its contact with the mucosa. In some embodiments, the mucoadhesive is selected from the group consisting of a hydrophilic polymer, a hydrogel and a thermoplastic polymer. Exemplary hydrophilic polymers include cellulose-based polymers (such as methylcellulose, hydroxyethyl cellulose, hydroxy propyl methyl cellulose, sodium carboxy methyl cellulose), a carbomer chitosan and plant gum. In some embodiments, the mucoadhesive is selected from the group consisting of poly(lactic acid) ("PLA") and poly(glycolic acid) ("PGA"), and copolymers thereof. In some embodiments, the mucoadhesive formulation includes a penetration enhancer such as sodium glycocholate, sodium taurocholate, L-lysophosphotidyl choline, DMSO and a protease inhibitor. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable carrier, a lipophilic micelle, a liposome, or a combination thereof. For example, the lipophilic micelle or liposome may comprise a ganglioside, a phosphatidylcholine, a phosphatidylserine, or a combination thereof. According to some embodiments, it can be desirable to prolong the residence time of the pharmaceutical composition, for example, to enhance absorption. Thus, the pharmaceutical composition can optionally be formulated with a bioadhesive polymer, a gum (e.g., xanthan gum), chitosan (e.g., highly purified cationic polysaccharide), pectin (or any carbohydrate that thickens like a gel or emulsifies when applied to nasal mucosa), a microsphere (e.g., starch, albumin, dextran, cyclodextrin), gelatin, a liposome, carbamer, polyvinyl alcohol, alginate, acacia, chitosans and / or cellulose (e.g., methyl or propyl; hydroxyl or carboxy; carboxymethyl or hydroxylpropyl), which are agents that enhance residence time in the nasal cavity. As a further approach, increasing the viscosity of the dosage formulation can also provide a means of prolonging contact of agent with olfactory epithelium. In one aspect of the disclosure, the methods recited herein comprise administration of a compound of Formula I as shown above. In a first embodiment of this aspect of the disclosure, the compound used with themethods disclosed herein is a compound of Formula I : or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R9, X, Y, and Z are as defined for Formula I. In a second embodiment of this aspect of the disclosure, the compound used with themethods disclosed herein is a compound of Formula I A: or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R9, X, Y, and Z are as defined for Formula I. In a third embodiment of this aspect of the disclosure, the compound used with themethods disclosed herein is a compound of Formula I B:

[0002] or a pharmaceutically acceptable salt thereof, where R1, R2, R3, R4, R5, R9, X, Y, and Z are as defined for Formula I. In a fourth embodiment, for the first through third embodiments above, X is O. In a fifth embodiment, for the first through fourth embodiments above, Y is O. In a sixth embodiment, for the first through fifth embodiments above, R5and R9are each independently hydrogen or -F. In a seventh embodiment, for the first through sixth embodiments above, R5is hydrogen or –F and R9is hydrogen. In an eighth embodiment, for the first through seventh embodiments above, R5and R9are each hydrogen. In a ninth embodiment, for the first through eighth embodiments above, R1, R2, R3, and R4are each independently hydrogen, -OH, -OC(O)(C1-C10 alkyl), or -OC(O)NH(C1-C10 alkyl). In a tenth embodiment, for the first through ninth embodiments above, R1, R2, R3, and R4are each independently hydrogen or –OH. In an eleventh embodiment, for the first through tenth embodiments above, R2and R4are each hydrogen and R1and R3are each –OH. In a twelfth embodiment, for the first through eleventh embodiments above, Z is wherein R10and R14are each independently hydrogen, -F, C1-C6 alkyl, C1-C6 haloalkyl, or - OH; R12is –F, -OH, -NH2, C1-C10 alkoxy, -OC(O)NH(C1-C10 alkyl), -OC(O)(C1-C10 alkyl), or -NH(S(O)0-2(C1-C10 alkyl)); and R11and R13are each independently hydrogen, -F, -OH, C1-C6 alkoxy, -OC(O)(C1-C10 alkyl), -OC(O)NH(C1-C10 alkyl) or C1-C6 haloalkoxy. In a thirteenth embodiment, for the twelfth embodiment above, at least one of R10and R14is -F. In a fourteenth embodiment, for the twelfth embodiment above, R10and R14are each hydrogen. In a fifteenth embodiment, for the twelfth through fourteenth embodiments above, R11and R13are each independently -OH or C1-C6alkoxy. In a sixteenth embodiment, for the twelfth through fifteenth embodiments above, R12is -OH. In a seventeenth embodiment, for the twelfth through sixteenth embodiments above, the compound is . Examples To assess the capacity of lead trihydroxyphenolic derivates to limit the development of IPF, we used a bleomycin mouse model. The bleomycin model has significantly contributed to understanding of fibrogenesis pathways in IPF (Jenkins et al.2017). This cost- effective system encompasses abnormal fibroblast proliferation and differentiation, increased deposition of extracellular matrix proteins, and damage to the alveolar architecture. It exhibits a 7-day inflammatory phase followed by a fibrotic phase. Spontaneous fibrosis occurs around 3-4 weeks post-intratracheal bleomycin (Kolb et al.2020). The overlap between the inflammatory and fibrotic phases is a key aspect for careful consideration in investigational approaches. Medicinal chemistry efforts have led to the development of a proprietary intranasal (IN) formulation of ABI-171((2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro-3,4-dihydroxy-5-methoxybenzoate). Pharmacokinetic studies with the IN formulation have demonstrated significantly elevated concentrations in the lungs. As such, the IN formulation was tested in both the preventative and therapeutic treatment studies for IPF using the bleomycin mouse model. Given that Pirfenidone is a current treatment for IPF, it was also included in both treatment studies. Preventing IPF with ABI-171 In this study, 30 male C57BL / 6J (Black 6) mice aged 9-10 weeks old were randomly assigned to five group: • Control – no treatment; • Bleomycin (BLM) - treated with vehicle; • Pirfenidone – (Oral, TD, 100mg / kg); • ABI-154 ((2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2,6- difluoro-3,4,5-trihydroxybenzoate )– (IN, QD, 60mg / kg); • ABI-171((2S,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl 2-fluoro- 3,4-dihydroxy-5-methoxybenzoate) – (IN, QD, 60mg / kg); The experiment considered the day of bleomycin injection as Day 0, treatments were started on Day 1 and harvesting was done on Day 21 (Figure 1A). The IPF model was successful induced through a single intratracheal infusion of bleomycin, and the experiment was successfully terminated at Day 21. IPF is associated with unexplained weight loss which was recapitulated in the BLM model (Figure 1B: labeled BLM for bleomycin and Control, ***P<0.001). In the group treated with IN ABI-171, there was significant increase in body weight from Day 14 to 21 (**P<0.01; ***P<0.001) and an improved change in body weight compared to the BLM group (Figure 1B: labeled BLM for bleomycin and 171 for ABI-171 treated, *P<0.05). This supports the potential for intranasal ABI-171 to limit the development of unexplained weight loss associated with IPF. IPF is characterized by the replacement of normal alveolar structure with collagen-rich matrix (McKleroy et al.2013). To explore the collagen deposition, we stained with hydroxyproline, which is a biomarker for collagen (Srivastava et al.2016) (Figure 1C). Compared with the BLM group, treatment with ABI-171 and ABI-154 significantly decreased the hydroxyproline content (Figure 1C: labeled BLM for bleomycin, 154 for ABI-154, and 171 for ABI-171) indicating a prevention of collagen deposition. In IPF the overproliferation of myofibroblasts, collagen, and extracellular matrix deposition is induced by a cascade of proinflammatory cytokine and chemokine secretion. These secreted chemokines and cytokines can recruit lymphocytes and neutrophils to the lungs which can further damage the tissue (Bhatia et al 2012). To assess the level of inflammation, we performed cell counts of lymphocytes (Figure 1D) and neutrophils (Figure 1E). Lymphocytes and neutrophils were significantly increased in the BLM group but were significantly reduced in the ABI-171 group (P <0.05) (Figure 1D-E: labeled BLM for bleomycin and 171 for ABI-171) indicating an anti-inflammatory effect of treatment. The change in collagen structure coupled with inflammatory activation leads to scarring of lung tissue as well as thickening and stiffening of the lung walls. To assess the fibrosis and lung tissue destruction, we stained the left lung with hematoxylin and eosin (H&E) (Figure 1F) and Masson’s trichrome staining (Figure 1G). After BLM treatment, a remarkable increase in alveolar septa thickening, as well as collagen deposition was observed (Figure 1G: labeled BLM for bleomycin), whereas drug with ABI-171 and ABI-154 had a reverse effect, with a gradual decrease in the alveolitis and pulmonary fibrosis degree relative to the BLM group (Figure 1G: labeled 154 for ABI-154 and 171 for ABI-171). Representative images indicating with arrows showing fibrosis and lung structure destruction are in Figure 1H. Treating IPF with ABI-171 Following the results of the preventative treatment study, we designed a follow up study in which drug treatment was done after 7 days from induction (Figure 2A). The treatment groups for this study are as follows: • G1: control; • G2: BLM treated with vehicle; • G3: pirfenidone (100mg / kg, TD, oral); • G4: EGCG (100mg / kg, QD, oral); • G5: ABI-171 (100mg / kg, QD, oral); • G6: ABI-171 (10mg / kg, QD, intranasally); • G7: ABI-171 (50mg / kg, QD, intranasally); We compared the activity of oral ABI-171 with two doses of IN ABI-171 as well as EGCG and pirfenidone. IPF has a poor prognosis with a mean survival of 2.5 years from the time of diagnosis (Frankel et al.2009). As such, we assessed the survival of the mice in the different groups. Interestingly, we observed that EGCG had a significantly lower survival rate (50% mortality, Figure 2B: labeled EGCG). However, both IN 50mg / kg and oral treatment with ABI-171 resulted in complete survival (Figure 2B: labeled 171 oral for orally administered ABI-171 and 171 IN for intranasally administered ABI-171). This demonstrates the potential for treatment with ABI-171 to improve survival in individual with IPF. Further, treatment with oral ABI-171 resulted in the recovery of animal body weight (Figure 2C: G5). Since unexplained weight loss is a symptom of IPF, this demonstrates the potential for treatment with ABI-171 to mitigate this symptom. We also did lymphocyte counts to assess the level of inflammation. Treatment with 100mg / kg oral ABI-171 or 50mg / kg IN ABI-171 significantly reduced lymphocyte cell counts compared to BLM model (Figure 2D: G2 for BLM, G5 for oral ABI-171 and G7 for 50mg / kg IN ABI-171). Given that a proinflammatory environment is part of the pathology for IPF, these data provide support for reducing inflammation associated with IPF. Similarly, 100mg / kg oral ABI-171 and 50mg / kg IN ABI-171 ameliorated the severity of BLM-induced lung injuries based on the H&E score (Figure 2E: G2 for BLM, G5 for oral ABI-171 and G7 for IN ABI-171) and the Masson’s score (Figure 2F: G2 for BLM, G5 for oral ABI-171 and G7 for IN ABI-171). Representative images indicating with arrows showing fibrosis and lung structure destruction are in Figure 2G. In addition to the accumulation of collagen, patients with lung disease have increased amounts of fibronectin, a glycoprotein that helps mediate the attachment of fibroblasts to the extracellular matrix, in their alveolar structures (Bitterman et al.1983). We assessed the levels of collagen and fibronectin in the previously mentioned groups using a fibronectin assay (Figure 2H), a collagen assay (Figure 2I) and a western blot (Figure 2J). Oral treatment with ABI-171 significantly reduced fibronectin levels relative to the BLM-induced increase (Figure 2H: G2 for BLM and G5 for oral ABI-171). Both IN doses and the oral dose of ABI-171 significantly reduced collagen levels relative to the BLM-induced increase (Figure 2I: G2 for BLM, G5 for oral ABI-171, G6 for 10mg / kg IN and G7 for 50mg / kg IN). Western blot analysis for fibronectin and collagen I for the previously mentioned groups. Treating NASH / Liver Fibrosis with ABI-171 To assess the general antifibrotic activity of ABI-171, we used the STAM mouse model. The STAM mouse model is a widely recognized model for studying non-alcoholic steatohepatitis (NASH) and liver fibrosis. This mouse model comprises exposing neonatal mice to low-dose streptozotocin and feeding them a high fat diet. (Fujii et al.2013). In this treatment paradigm mice were untreated, orally administered the PEG400 vehicle alone or with ABI-171 (Figure 3A: Normal for untreated, SMC + vehicle for vehicle treated STAM mice, SMC + ABI-171 for ABI-171 treated STAM mice). The oral dose of ABI-171 was 100mg / kg, OS, QD, 4-week treatment between the age of 6 to 10 weeks. Oral ABI-171 treatment resulted in reduced liver fibrosis compared to vehicle treated STAM mice (Figure 3A). Representative photomicrographs of stained liver tissue also show reduced fibrosis around the central vein for ABI-171-treated STAM mice compared to vehicle-treated (Figure 3B: Middle panel for vehicle-treated and right panel for ABI-171-treated). Efficacy of ABI-171 in the Methionine-Choline-Deficient (MCD) Diet-Induced NASH Mouse Model The efficacy of ABI-171 in treating liver fibrosis was further evaluated in a methionine-choline-deficient (MCD) diet-induced non-alcoholic steatohepatitis (NASH) mouse model. Male C57BL / 6 mice (5 weeks old, n=6 per group) were fed an MCD diet for 6 weeks to induce NASH, with oral administration of ABI-171 (50 mg / kg, daily) or EGCG (50 mg / kg, daily) as a positive control from weeks 3 to 6. Control groups included normal diet + vehicle and MCD diet + vehicle. Histopathological analysis using Masson’s trichrome staining revealed a significant reduction in collagen deposition in the ABI-171-treated group (****P<0.0001 vs. MCD + vehicle, one-way ANOVA), indicating a robust anti-fibrotic effect (Figure 4 A and 4B). Hematoxylin and Eosin (H&E) staining further demonstrated significant reductions in steatosis, lobular inflammation, and hepatocellular ballooning (***P<0.001, ****P<0.0001 vs. MCD + vehicle) (Figure 4D). Serum free fatty acid (FFA) levels were significantly reduced in the ABI-171 group (**P<0.01) compared to the MCD + vehicle group, with a stronger effect than EGCG (*P<0.05) (Figure 4C). A positive trend in liver FFA reduction was also observed, though not statistically significant. These results suggest that ABI-171’s anti-fibrotic and anti-inflammatory effects in liver fibrosis aremediated, at least in part, by potent inhibition of PIM1 / DYRK1A (IC : 87 nM / 73 nM forABI-171 vs. 1359 nM / 235 nM for EGCG) and potential modulation of LOXL2 / TGF-pathways, consistent with findings in the bleomycin-induced IPF model (see Figure 2). The superior bioavailability of ABI-171 (16% vs.2% for EGCG) likely contributes to its enhanced therapeutic efficacy. These findings support the use of ABI-171 for treating liver fibrosis and related NASH pathologies. Reference Araldi, G.L., Hwang, Y.-W., & Raghu, G. (2024). Development and Evaluation of ABI-171, a New Fluoro-Catechin Derivative, for the Treatment of Idiopathic Pulmonary Fibrosis. International Journal of Molecular Sciences, 25, 11827

Claims

We claim:

1. A method of treating or limiting development of fibrotic disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I:or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4are each independently hydrogen, halogen, -NO2, -CN, C1-C10 alkyl, C1-C10 haloalkyl, -NH2, -NH(C1-C10 alkyl), -N(C1-C10 alkyl)2, -OH, C1-C10 alkoxy, C1-C10 haloalkoxy, -SH, hydroxy(C1-C10 alkyl), alkoxy(C1-C10 alkyl), amino(C1-C10alkyl), -CONH2, -CONH(C1-C10alkyl), -CON(C1-C10alkyl)2, -OC(O)NH2, -OC(O)NH(C1-C10alkyl), -OC(O)N(C1-C10alkyl)2, -CO2H, -CO2(C1-C10alkyl), -CHO, -CO(C1-C10alkyl), -OC(O)(C1-C10alkyl), -S(O)0-2(C1- C10alkyl), or -NH(S(O)0-2(C1-C10alkyl)); R5and R9are each independently hydrogen, halogen, -NO2, -CN, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -OH, C1-C6alkoxy, C1-C6haloalkoxy, or -SH; R7is hydrogen, halogen, -NO2, -CN, C1-C10 alkyl, C1-C10 haloalkyl, -NH2, -NH(C1- C10 alkyl), -N(C1-C10 alkyl)2, -OH, C1-C10 alkoxy, C1-C10 haloalkoxy, -SH, hydroxy(C1-C10 alkyl), alkoxy(C1-C10 alkyl), amino(C1-C10 alkyl), -CONH2, -CONH(C1-C10 alkyl), -CON(C1-C10 alkyl)2, -CO2H, -CO2(C1-C10 alkyl), -CHO, -CO(C1-C10 alkyl), -S(O)0-2(C1-C10 alkyl), or -NH(S(O)0-2(C1-C10 alkyl)); R6and R8are each independently hydrogen, halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or -SH; X is O or C; Y is O or NH; andwherein R10and R14are each independently hydrogen, halogen, -NO2, -CN, C1-C6alkyl, C1-C6haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -OH, C1-C6 alkoxy, C1-C6 haloalkoxy, or -SH; R12is hydrogen, halogen, -NO2, -CN, C1-C10 alkyl, C1-C10 haloalkyl, -NH2, -NH(C1-C10 alkyl), -N(C1-C10 alkyl)2, -OH, C1-C10 alkoxy, C1- C10 haloalkoxy, -SH, hydroxy(C1-C10 alkyl), alkoxy(C1-C10 alkyl), amino(C1-C10 alkyl), -CONH2, -OC(O)NH(C1-C10 alkyl), -CON(C1- C10 alkyl)2, -CO2H, -CO2(C1-C10 alkyl), -CHO, -OC(O)(C1-C10 alkyl), -S(O)0-2(C1-C10 alkyl), or -NH(S(O)0-2(C1-C10 alkyl)); R11and R13are each independently hydrogen, halogen, -NO2, -CN, C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6alkyl), -N(C1-C6alkyl)2, -OH, C1-C6alkoxy, C1-C6haloalkoxy, -SH, OC(O)(C1-C10alkyl), or -OC(O)NH(C1-C10alkyl);n is 0–4; and each R15is independently C1-C6 alkyl, C1-C6 haloalkyl, -NH2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -OH, C1-C6 alkoxy, or C1-C6 haloalkoxy;, wherein R16is hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, -OH, C1-C6 alkoxy, or C1- C6 haloalkoxy;R17is hydrogen, C1-C6 alkyl, or C1-C6 haloalkyl. The method of claim 1, wherein the method comprises treating fibrotic disease in a subject with fibrotic disease.

3. The method of claim 1, wherein the method comprises limiting development of fibrotic disease in a subject at risk of developing fibrotic disease.

4. The method of any of claims 1-3, wherein the fibrotic disease is selected from the group consisting of idiopathic pulmonary fibrosis (IPF), liver fibrosis, chronic kidney disease (CKD), uterine fibrosis, and ovarian fibrosis.

5. The method of claim 4, wherein the fibrotic disease comprises IPF.

6. The method of claim 5, wherein the method comprises treating IPF in a subject with IPF.

7. The method of claim 6, wherein the treating comprises conferring to the subject one of more benefits selected from the group consisting of reducing pulmonary inflammation, reducing lung scarring, improving progression free survival, improving 6-minute walk distance, improving forced vital capacity (FVC), delaying need for lung transplantation, limiting development of pulmonary hypertension, limiting development of respiratory failure, limiting development of lung cancer, limiting development of right sided heart failure and recovering lost body weight.

8. The method of claim 5, wherein the method comprises limiting development of IPF in a subject at risk of developing IPF.

9. The method of claim 8, wherein the subject has one or more risk factors for IPF selected from the group consisting of age 70 or older; a family history of IPF; mucin 5B (MUC5B) rs35705950 locus (gain-of-function promoter variant) single nucleotide polymorphism; cigarette smoking; previous infection with one or more of Epstein-Barr virus, Influenza virus, Herpesviruses or Hepatitis C virus; and gastroesophageal reflux disease (GERD).

10. The method of claim 4, wherein the fibrotic disease comprises liver fibrosis.

11. The method of claim 10, wherein the method comprises treating liver fibrosis in a subject with liver fibrosis.

12. The method of claim 11, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of limiting development of liver cirrhosis, limiting development of liver failure, limiting development of portal hypertension, delaying need for liver transportation, reducing ascites, limiting development of hepatic encephalopathy, limiting development of hepatorenal syndrome, and reducing variceal bleeding.

13. The method of claim 10, wherein the method comprises limiting development of liver fibrosis in a subject at risk of developing liver fibrosis.

14. The method of claim 13, wherein the subject has one or more risk factors for liver fibrosis selected from the group consisting of autoimmune hepatitis, biliary obstruction, iron overload, nonalcoholic fatty liver disease, Hepatitis B virus, Hepatitis C virus, and long-term excesses of drinking alcohol.

15. The method of claim 4, wherein the fibrotic disease comprises CKD.

16. The method of claim 15, wherein the method comprises treating CKD in a subject with CKD.

17. The method of claim 16, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of slowing progression to end-stage renal disease (ESRD), delaying initiation of long-term dialysis, delaying need for kidney transplantation, increasing estimated glomerular filtration rate (eGFR), reducing urine albumin-creatine ratio (UACR) and normalizing proteinuria.

18. The method of claim 15, wherein the method comprises limiting development of CKD in a subject at risk of developing CKD.

19. The method of claim 18, wherein the subject has one or more risk factors for CKD selected from the group consisting of age 60 or older, diabetes, heart disease, a family history of CKD or renal failure, inherited kidney disorders, past damage to kidneys and smoking or tobacco use.

20. The method of claim 4, wherein the fibrotic disease comprises uterine fibrosis.

21. The method of claim 20, wherein the method comprises treating uterine fibrosis in a subject with uterine fibrosis.

22. The method of claim 21, wherein treating comprises conferring to the subject one or more benefits selected from the group consisting of delaying need for surgical intervention, reducing fibroid volume, and reducing menstrual bleeding.

23. The method of claim 20, wherein the method comprises limiting development of uterine fibrosis in a subject at risk of developing uterine fibrosis.

24. The method of claim 23, wherein the subject has one or more risk factors for uterine fibrosis selected from the group consisting of age 40 or older, premenopausal state, family history of uterine fibroids, hypertension, frequent consumption of soybean milk and parity.

25. The method of claim 4, wherein the fibrotic disease comprises ovarian fibrosis.

26. The method of claim 25, wherein the method comprises treating ovarian fibrosis in a subject with ovarian fibrosis.

27. The method of claim 26, wherein the treating comprises conferring to the subject one or more benefits selected from the group consisting of reducing ovarian chocolate cyst formation, limiting development of polycystic ovarian syndrome (PCOS), limiting premature ovarian failure, and limiting development of ovarian cancer.

28. The method of claim 25, wherein the method comprises limiting development of ovarian fibrosis in a subject at risk of developing ovarian fibrosis.

29. The method of claim 28, wherein the subject one or more risk factors for ovarian fibrosis selected from the group consisting of previous history of surgery, inflammation, and immune abnormalities.

30. The method of any one of claims 1-29, wherein the compound is administered orally.

31. The method of any one of claims 1-29, wherein the compound is administered intranasally.

32. The method of any one of claims 1-29, wherein the compound is administered by inhalation.

33. A method for treating or limiting the development of one or more of pulmonary inflammation, lung scarring, pulmonary hypertension, respiratory failure, ESRD, ovarian chocolate cysts, PCOS, ovarian failure, ovarian cancer, cirrhosis, liver failure, portal hypertension, ascites, hepatic encephalopathy, hepatorenal syndrome, and variceal bleeding comprising administering to a subject in need thereof a therapeutically effective amount of ABI-171.

34. The method of any one of claims 1-33 wherein the compound is of Formula I :or a pharmaceutically acceptable salt thereof.

35. The method of claim 34 wherein the compound is of Formula I A:or a pharmaceutically acceptable salt thereof.

36. The method of claim 34 wherein the compound is of Formula I B:or a pharmaceutically acceptable salt thereof. The method of any one of claims 34-36 wherein X is O.

38. The method of any one of claims 34-37 wherein Y is O.

39. The method of any one of claims 34-38, wherein R5and R9are each independently hydrogen or -F.

40. The method of any one of claims 34-39, wherein R5is hydrogen or –F and wherein R9is hydrogen.

41. The method of any one of claims 34-40, wherein R5and R9are each hydrogen.

42. The method of any one of claims 34-41, wherein R1, R2, R3, and R4are each independently hydrogen, -OH, -OC(O)(C1-C10 alkyl), or -OC(O)NH(C1-C10 alkyl).

43. The method of any one of claims 34-42, wherein R1, R2, R3, and R4are each independently hydrogen or –OH.

44. The method of any one of claims 34-43, wherein R2and R4are each hydrogen and R1and R3are each –OH.

45. The method of any one of claims 34-44 wherein Z iswherein R10and R14are each independently hydrogen, -F, C1-C6 alkyl, C1-C6 haloalkyl, or - OH; R12is –F, -OH, -NH2, C1-C10 alkoxy, -OC(O)NH(C1-C10 alkyl), -OC(O)(C1-C10 alkyl), or -NH(S(O)0-2(C1-C10alkyl)); and R11and R13are each independently hydrogen, -F, -OH, C1-C6alkoxy, -OC(O)(C1-C10alkyl), -OC(O)NH(C1-C10alkyl) or C1-C6haloalkoxy.

46. The method of claim 45 wherein at least one of R10and R14is -F.

47. The method of claim 45, wherein R10and R14are each hydrogen.

48. The method of any one of claims 45-47, wherein R11and R13are each independently -OH or C1-C6 alkoxy.

49. The method of any one of claims 45-48, wherein R12is -OH.

50. The method of any one of claims 45-49, wherein the compound is(ABI-154) (ABI-171)

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