CRC3SS-EEFERENGE TO RELAXED APPLICATIONS

This application claims the priority benefit of G.S. Provisional Application No, 62/607,485, filed December 19, 2017: the entire content of whicbis herein Incorporated by reference.

HELD OF THE INVENTION

The present invention relates to novel substituted isoxazo!e compounds _* compositions containing them, and methods of using them, for example, for the treatment of disorders associated with one or more of the lysophosphatidic acid (LPA) receptors.

BACKGROUND OF THE ίNUTN ^' ϊ ION

Lysophospholipids are niembraoevferived bioaciive lipid mediators, of which one of the mos medically important is lysophospbatldle acid (LPA). LE A is not a single molecular entity hot a collection of endogenous structural variants with fatty acids of varied lengths and degrees of saturation (Fivjiwara et ai., JBiol Cheer, 2CK1S, 280, 35038- 35050). The structural hacfcbone of the LPAs is derived from glyeerohbased

phospholipids such as phosphafidyleholme (PC) or phosphatidie aci (PA).

The LPAs are bioactive lipids (signaling lipids) that regulate various cellular signaling pathways by binding to the same class of 7-transm braiie domain G protein- coupled (GFQl) receptors (Chou, J, _: , H!a, T _> , Spiegel. S,, Moolenaar, W., Editors, Lysophospkolipid Receptors: Signaling arid Biochemistry, 201.3, Wiley; ISBN; ^78-0- 470-5690.5-4 & Zhao _* Y. et ah Biochim, Biophys. Ada (BBAfMol Ceii Biol Of Lipids, 2013, l/, 86-92). The currently known LPA receptors are designated as LPAx, LPAs,

LPAs, LPA-i, .LPAs an LPAs (Choi, X. W., Anmt. Rev. Pharmacol Toxicol, 2010, 56, 157-1.86; Klhara, Y., et al, Itit J, Pharmacol., 2014, i i . 3575-3594).

The LPAs have long been known as precursors of phospholipid biosynthesis in both eukaryotic and prokaryotic cells, but the LPAs have emerged only recently as signaling molecules that axe rapidly produced and released by activated cells, notably platelets, to influence target cells by acting on specific cell-surface receptors (see, e.f. , Moolenaar et al, BioEssays, 20114, 26, 870-381 , and van Leewen et a.l, Biochem. Soc. Tmm , 2003, 31, 1209-1 12), Besides being synthesised and processed to mot® complex phospholipids in the endoplasmic reticulum, LPAs can be generated through the hydrolysis of pre-existing phospholipids following cell activation for example, the sn-2 position is commonly missing a fatly add residue doe to deacyisfion, leaving only the sn- 1 hydroxyl esfonfsed to a fatty add. Moreover, a key enxytue in the production of LPA, autotaxin (IysoPLD/NPP2), may be the product of an oncogene, as many tumor ty pes up·· regulate rotaxin (Brindley, D., J Cell Biochem 2004, .92, 900-12). The concentrations ofLPAs in human plasma & seriun as well as human bronchonlveolar lavage fluid (BALF) have been reported, inoluding deierrumaiians made nslng sensitive an specific LC/MS & LC/MS/MS p ocedntes (Baker ct ah Ami Biochem , 2901, 292, 287-295; Onorato et aL J. Lipid Res , 2014, 55, 1784-1796).

LPA influences a wide range of biological responses, ranging from induetiors of cell proliferation, sti ulation of cell .migration and nenrite retraction, gap j unction closure, and even slime mold ehetnotaxis (Goet , et al , Scientific World J, 2902, 2, 324- 338; Chun, L, Hla, T. _s Spiegel, S., Moolenaar, W , BdLms, IgsaphosphoUpid R ep rs: Signaling and Biochemistry , 2013, Wiley; ISBN: 978-0-4?O~5690S-4}. The body of knowledge about the biology of LPA continues to grow as more and more cellular systems are tested for LPA responsiveness. For instance, it is now known that, in additionto stimulating cell growth and proliferation, LPAs promote cellular tension and cell- surface fibronecd binding, which are important events in wound repair and regeneration (Moolenaar et ah, BioEssays, 2004, 26, §70-881). Recently, anti-apoptotic activity has also been ascribed to L PA, and it has recently been reported that PPARy is a

receptor/target for LPA (Simon et aL, Biot. Chem ., 2005, 59, 14656-14662).

Fibrosis is the result of an uncontrolled tissue healing process leading to excessive accumulation and insufficient resorption of extracellular matrix (ECM) which ultimately results in end-organ fail ore (Rockey, D. C., et ai, New Engl J Med, 2015, 572, 1 138- 1 149). The LPA* receptor has been reported to be over-expressed in idiopathic pulmonary fibrosis (IPF) patients. LPA] receptor knockout mice were protected fro bleomycin- Induced lung fibrosis (Tager et ai, Nature Med, 2008, 14, 45-54), The LPA* antagonist BMS-9S602O was shown m slum ikandy reduce the rate ofFVC (forced vital capacity) decline in a 26-week clinical trial in IPF patients (Palmer et ai, Chest, 2018, 154, 1061 - 1069). LPA pathway inhibitors (e.g. an LPAs antagonist) were shown to be chemoprevenitve anti-fibroiie agents in the treatment of hepatocellular carcinoma in a rat mode! (Nafcagawa ei at., Cance Celt. 2111 ft, 30, K29-S90).

Thus, antagonizing the LPA* receptor may be useM for the treatment of fibrosis such as pulmonar fibrosis, hepatic fibrosis, renal fibrosis, arterial fibrosis and systemic sclerosis, and thus the diseases that result from fibrosis (pnl oftary fibrosisfidlopailue Pulmonary Fibrosis [IFF], hepatic fibrpsis-Non-akobohc Sicatohepatitls [MASH], renal fibrosis-diabetic nephropathy, systemic selemsis-sekroderma, etc.).

SUMMARY OF THE INVENTION

The pres erst invention provides novel substituted isoxazote Co pounds including stereoisomers, tautomers, and pharmaceutically acceptable salts or solvates thereof, which are useful as antagoni sts against one or more of the lysopbosphatidic acid (LPA) receptors, especially the LPAi receptor.

The present invention also provides processe and intermediates lor making the compounds of the: present invention.

The present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one of the compounds of the present invention or stereoisomers, tautomers, pharmaceutically acceptable salts or solvates thereof

The compounds of the invention may be use in the treatment of conditions in which LPA plays a role.

The compounds of the present invention may be used in therapy.

The compo unds of the present invention ma be used for the manufacture of a medicament for the treatment of a condition in which inhibition of the physiological activity of LPA is useful, such as diseases in which an LPA receptor participates, is involved In the etiology or pathology of the disease, or is otherwise associated with at least one symptom of the disease.

In another aspect, the present invention is directed to a method of treating fibrosis of organs (liver, kidney, lung, heart and the like ns well as skin), liver diseases (acute hepatitis, chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerati e failure, non-alcoholic steatohepati l f ASHT Us er bvpoiuncsioo. hepatic blood flo disorder, and the 11 keg cell proliferative disease [cancer (solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi’s sarcoma, leukemia, chronic lymphocytic leukemia (€LL) and the like) atxd vasi e metastasis: of cancer ceil, and the like], ftammatwy disease (psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract disease (irritable bowel syndrome (IBS), inflammatory bowel disease (IBBO, abnormal pancreatic secretion, and the like), renal disease, -urinary tract- associated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract, and the like), inflammatory disease of lower urinary tract, dysuria, frequent urination, and the like), pancreas disease, abnormal angiogenesis-associated disease

(arterial obstruction and the like), scleroderma, brain-associated disease (cerebral infarction, cerebral hemorrhage, and the like), neuropathic pain, peripheral neuropathy, and the like, ocular disease (age-related macular degeneration (AMO), diabetic retinopathy, proliferative viireomtiaopaihy (PVR), cicatricial pemphigoid, glaneonm filtration surger scarring, and the like)

in another aspect, the present invention la directed to a method of treating diseases, disorders or conditions in which activation of at least one I, PA receptor by LPA contributes to the symptomology or progression of the disease, disorder or condition. These diseases, disorders, or conditions may arise from one or more of a genetic, iatrogenic, immunological, infectious, metabolic, oncological, toxic, surgical, and/or traumatic etiology.

In another aspect, the present in vention is directed to a method of treating renal fibrosis, pulmonary fibrosis, hepatic fibrosis, arterial fibrosis and systemic sclerosis comprising administering to a patient in need of such treatment a compound of the present invention as described above.

In one aspect, the present invention provides methods, compounds,

pharmaceutical compositions, and medicaments described iwrein that comprise antagonists of LPA. receptors, especially antagonists of LPA i.

The compounds of the invention can be used alone, in combination with other compounds of the present invention, or in combination with one or more, preferably one to two other agenfrs). These and other features of die invention will be set forth in expanded form as the d Isciosure continues.

DETAILED DESCRIPTION OF THE INVENTION l COMPOUNDS OF THE INVENTION

In one aspect, the present invention provides, inter dia, compounds of Formula

or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein

XL XL X\ nd X ⁴ are each independently ON or N; provided that no more than two pf ^ X X ³ , or X ⁴ are N;

L Is a covalent bond or CM ai ylene substituted with 0 to 4 RL

Z is CHR ^Sa , NR ^® * or 0;

the Y ring is a S-membered heteroaryi or Sn onbered heierocyelyl, each of which independently contains one nitrogen atom and at least one other heteroatom selected font nitrogen, oxygen, and sulfur;

R* is (-€%) _& R ⁹ ;

a i an integer of f ⁾ or 1 ;

E ² is each independently halo, cyaoo hydroxyl amino, CM alkyl. CM cycloalkyl 4 to Omeoibered heterocyeiyl, alkylanimo, haloalkyi, liydroxyalkyi aminoalkyl, aikoxy, alkoxya!kyi haloaikoxyalkyl or ha!oalkoxy;

n is an integer of 0, 1 , or 2; 85 is halo, cymo, hydroxyl, anhno, oxo, -ORl ~8R ³ , S,^NR¾l NH _{5 ~} MOH,

(felly or partially deutemtod), Cos heieroaikyl, 6~ to 10-membere aryl, arylalkyl 5- to 1 O-membered heteroaryl heleroaryMky 3- to: B- embered caxbooyclyl

carhoeyoM ikyl, 4-· to S- embered heteroeyclyl or heterocycMaikyk wherein the alkyl, heteroalkyl, aryl, heteroaryl carhoeyc!yl heteroeydyi and R ^B , by themselves or as part of another group, are each independently substituted with 0 to 5 Rl

R ^® is selected from CM: alkyl Cw deuteraied alkyl (.felly or partially demerated), haloalkyl hydroxyalkyl aminoalkyl, alkoxyaikyl haloalkoxyalkyl aryl, arylalkyl heteroaryl, heleroary!alkyl carbocydlyi carhoeyehdalkyl, haieroeyelyl, and

heteroeyelylaik l;

R ^fe is each independently hydrogen or R ^a :

R ^® is each independently Rl o alternatively , two R ^E , taken together with the nitrogen atom to which they are attached, ferai 4~ to 7-membered heteroeydyi;

R° is each independently selected from R ^a , alkoxy, haloalkoxy, alkylamino, cyeioalkylamino, heterocycMamfeo, haloalkyl hydroxyalkyl, am oalkyl cydoalkoxy, heteioeyciyloxy, haloalkoxy, alfcoxyalkoxy, haloalkylaxnino, alkoxyalkylarnino, haloalkoxyalkyisnnno, arylammo, aralkylamino, aryloxy, aralkyloxy, hetetoaryloxy heteroarylalkytoxy, alkylthio, halo, cyan», hydroxyl amino, oxo, -OR ^® , -SRI ^::: S, ~NR ³ Rl

-NR€( 0)NR ^c Rl fC€(NR ^b )Rl and -HR ^b €(NR ^b )NR ^c R ^c ; or alternatively one or two R ⁴ on alkj l heieroaikyl aryl heteroaryl, earbocyclyl or heteroeydyi taken together with the a o s to svhich the R ^d is attached, form a cyclic or bridge moiety;

R ⁴ is each independently halo, hydroxyl, cyano, CM alkyl, CM haloalkyl

Cxs alkoxy alkyl. C alkoxy, oxo (~0), or imino ( NH);

m is an integer of 0, I , or 2;

R and R ⁶ are each independently hydrogen halo, cyano, hydroxyl amino. C _{l -#} alkyl, alkyiamino, haloalkyl hydroxyaikyk aminoalkyi, afkoxya!kyl, Moaikoxyalkyi alkoxy, or h&foa koxy

R ^? is halo, i o. eyaho, hydroxyl amino, alkyl, CM eyeloalkyl, 4 to 6- membered heierocyclyi alkyiamino, haloalkyl, hydroxyalkyl, aminoalkyi, alkoxyaikyt

$ hsdoalkoxyalkyl alkoxy, or oa!koxy:

R ^¾a is hydrogen, halo, eyano, or C alkyl;

R ^Sb is hydrogen or C alkyl;

R ^¾ is selected Com --CN _! --C(0)0R ^Ki , ~€(0)Ήί& ^h *& \

0 R ^e is CM alkyl, haloalkyl, hydroxyalkyl, aminoalkyi, alkoxyalkyl, or

haloalkoxyalkyl;

R ^J!) is hydrogen or Cwo alkyl; and

R ^Us and R ^{f ii>} are each independently hydrogen, C _M alkyl. C ; eyeloalkyl 4 to 6- embered heierocydyl, alkyiamino, haloalkyl, h droxyalkyl , ammoalkyl, alkoxyalkyl,S haloalkoxyaikyl, alkoxy, of baloalkoxy.

In. one embodiment of Formula (la) or (lb), X ² Is CR , where * is hydrogen or CM alkyl (e.g., methyl).

In any one of the preceding embodiments of Formula (la) or (lb). R ^S is hydroge or C _M alkyl

0 In any one of the preceding embodimen ts of Form ula (la) or (lb),

moiety is

Y\ Y and Y* are each indepen ently selected from C or N nd the dashed circle denotes optional bonds; and the 5-member ring .formed by CYl Y% Y ^JK , Y% and Y ^s ) and (Y ^! , Y ^2a , Yd Y ⁴ , and Y ⁵ ) can be either aromatic Or nonaromaiic;

Yy Y· Y and Y ⁵ are each independently selected from C, CR ^4a , N, NR ⁴⁹ , S, or

0; with the provisos that (I ) at least one of;(Y ^! , Yfr Y ^3a , Y ⁴ , and Y ⁵ ) or til least one of (Yl \ Y\ Y ⁴ , and Y ^s ) is N or NR ⁴³ , and (2) at least one of (Y ¹ , Y y Y Y ⁴ , and Y ³ ) or at least one of (Yl Y ^2a , Y ³ , Y ⁴ , and Y ⁵ } is C or€E ⁴ k

R ^4S is each independently hydrogen, halo, oxo, iinino, CM alkyl, C _M feabaikyl, Z altocssyalkyl, C] a alkoxy; and

R"* is each independently hydrogen or CM alkyl

In any one of the preceding embodiments of Formula (la) or (lb),

R ² is halo, cyano, hydroxyl, amino, -OR* -SR ³ , -NROC, Coe alkyl.

Cor heteroalkyi, 6- to lO-membered aryl, aryl alkyl, 5- to !O-membered heteroaryl heteroatylalkyl 3- to 8-membered earboeyclyi, earbocydyialkyl, 4- to 8-merobered heierocyclyl, or heterocyc!yi alkyl; wherein the alkyl heteroalkyl aryl, heteroaryl, earboeyclyi, heierocyclyl an 1C, by themselves or as part of another group, are each independently substituted with 0 to 5 R ^d ;

R. ⁸ is selected from C alkyl, haloa!ky!, hydroxyalkyl, anihioalkyL alkoxyalkyl, Imioalkoxyaikyl, aryl, aryialk !, heteroaryl, heteroarylalkyl earboeyclyi,

earbocydyialkyl heierocyclyl and heterocyciylalkyl;

9 is each Independently hydrogen or RY

R ^c is each independently R ^b ; or alternatively, two Retaken together with the nitrogen atom to which they am attached. form a 4- to 7-me bered heteroeyclyi;

ll ^li Is each independently selected from R ^K , alkoxy, haloalkoxy, alkyhtmino.

cyc.loalkylammo _» heterocye!y famine, haloalkyl, hydroxyalkyl, armnoalkyl cycloaikoxy, heterocydyioxy, haloalkoxy, alkoxyaikoxy, haloalkylamino, alkoxyaikyiammo, haioalkoxyalkylamino, ar ianhno, aralkylanuno, aryioxy, araikyloxy, heteroaryioxy, heteroaryialkyloxy, alkylthio, halo, cyano, hydroxyl, a ino, oxo, -ORfr -SRI

and ~NR ^c Rh or alternatively one or two E ^d on alkyl hetcroalkyl aryl, heteroaryl carboeydyl, or heterocyelyl, taken together with the atoms to which the R ⁴ Is attached, form a cycle or bridge moiety.

I» any on© of the preceding embodiments of Formula (is) or (lb) , the compoun is represented by Formula (11a) or (lib):

Y Y ^2s , and are each independently selected fem C or N;

Y) Ύ ⁴ , and U ^' are each independently selected from C ^' , CR ⁴⁸ , N, NR ^4t YS, or O: wi th the provisos that (I } at!east one of ( Y ⁵ , Y~, Y ^a , Y ⁴ and YY or at least one of ( Y ¹ , Y ^2s , Y ³ , Y"l and Y ^s ) k N or R ⁴ ) and (2) at least one of (Y Yl Y ^¾ \ Y ⁴ , and ⁴ } or at least one of (Y( Y ² h Yh Y ⁴ , and Y ⁴ ) is C or CR ^a ; and the dashed circle denotes optional bonds; and the S-member ring formed by (Y) Y ² , Y _y Y ⁴ , and Y") and ( Y*. Y ^2iS _s Y ³ , Y ⁴ , and Y ³ ) can he either aromatic or nonaro.matic;

R ⁴ * is each independently hydrogen, halo, Cos alkyl. C haloalkyi (Ys alkoxyalkyL C _M alkoxy, oxo, or imino;

R ^4t> is each independently hydrogen or C alkyl;

RY is each independently hydrogen, halo, cyano, hydroxyl amino, Cos alkyl.

Ch-s cydoalkyl, aikylamino, haloalkyi, hydroxyalkyl, aminoalkyl, aikoxyalkyl, hafoalkoxyalkyl, alkoxy, or haloalkoxy;

f is an integer of 0, 1, or 2;

Z Is C¾ or NR ^SS : with the proviso that when Z is NR ^¾! \ Y ¹ is C;

n is 0 or 1 ; and

E.( R ² , rt, R ³ , R) R ^Sb , Xl X ² , X ³ , and X ⁴ are the same as defined above.

In one embodiment of Formula (lia) or (lib), X is CR.% where R ⁴ Is hydrogen or

CM alkyl In any one of the preceding embodiments of Formula (lia) or (lib), X ³ is N In any one of the preceding embodiments of Formula (lia) or (lib),

\ R is eaeh independently halo, eyano, hydroxyl amino.€i-c _> alkyl alkyiamlno f ioalkyi hydroxyalkyl, aminoalkyL alkoxyalkyi haloalkoxyaikyl alkosy, or haloalkoxy; and d is m integer of 0, 1, or 2

In any one of the preceding embodiments of form ala (!la) or (fib).

Y ³ , Y , and Y are each independently€, CR ⁴ *, , O or S.

in. any one o f the preceding embodiments of Formula (Ha) or (li b).

the moiety is

In any one of the preceding embodiments of Formula (II a) or (Tib),

the

In any one of the preceding embodiments of Formula (Ila) or u lhi. R ^' Hs hydrogen.

In any one of the preceding embodiments of Formula (Ila) or (lib), K. ^! is Ci¾ .

In one embodiment. R ³ is hydrogen.

In any one of the preceding embodiments of Formula (Ila) or (Oh), the compound Is represented by Formula CUD:

Y ^¾ , U ⁴ , and U are e ch independently selected from C. CRfo NR S, or O; with the prdViso that: at least one of Yy Yfo Y ⁴ , and Y ⁵ is N or R ⁴ ; and tbs dashed circle denotes optional bonds forming an aromatic ting; R ^4a is each independently hydrogen, halo, <¾. ₄ alkyl CM h oalkyl, CM alkoxyalkvi or CM alkoxy; R; ^fe is each independently hydrogen or C alkyl; R ^ist is hydrogen, chloro, rinoro. or C alkyl; and

Rl R:1 !Y Xy X ³ , and X ⁴ are the same a defined above

In any one of the preceding embodiments of Formula (III), the

In one embodiment, is hydrogen.

In any one of the preceding embodiment of Formula Oil), R* is CCfil 1

In any one of the preceding embodiment of Formula (III),

methyl or ethyl.

in any one of the preceding embodiment of Formula (111),

the moiety is

each independently€, N, O ui S

la any one of the preceding embodiment of Formula (HI),

In any one of the preceding embodiment of Formula (III),

2 is halo, cyano, hydroxyl, ammo, -OR*, -SRf ~NR ^¾ R ^i; , Cm alkyl. Chw haloalkyl, C _\ ..¾ heteroaikyl, 6 to 10-membered aryl, aryiaikyL 5- to 10- embered heteroaryl, heieroary!alkyi, 3- to 8-membemd earfeoeyclyi, earboeyclylalkyi 4- to 8~ omb«red heterocy yl, or hetcrocyclyialkyl: wherein the alk l, heteroaikyl, aryl, heteroaryl, carhocyclyi, heterocyoiyl, an R*, by themselves or as part of another poop, are each independentl substituted with 0 to S K ^d In one embodiment, the alkyl is a fully or partiall denterated alkyl

R* is selected from C _. ; alkyl, haloalkyl liydroxyalkyi ammoalkyl, a!koxyalkyl, haloalkoxyaifcyL aryl arylalkyl, heteroaryl, heteroarylalkyl, earboeyelyi,

carbocyc!yialkyl, heterocydyl, an heterocyclylalkyl;

b Is each independently hydrogen or II ^s ;

R ^i; is each independently R’k or alternatively, two R ^c , taken together with the nitrogen atom to which they are attached, form a 4~ to 7~membered heterocyelyl;

R ² i.s each independently selected from R ⁸ , alkoxy, haloalkoxy, alkyla o, cycloalkylamino, heterocycly ino, haloalkyl, hydraxyalkyl, aminoalkyl, cyeloa!koxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkyiam o, alkoxyalkylamhio, haloalkoxyalkylamino, ary I amino, aralkyl ansino, ary!oxy, aralkyloxy, heieroaryloxy, heieroarylalkyloxy, alkylthio, halo, eyano, hydroxyl, amino, oxo, -OR ⁸ , -Silk

and -MRflly or alternatively one or two B.:· on alkyl, lieteroalkyl aryl, heteroaryl, earbocyelyl, r heterocyclyl, taken together with the atoms to which the R. ^d is attached, form a cyclic· or bridge oiety

In any one of the preceding embodiment of Formula (III),

R ³ is CM alkyl, C haloalkyl CM alkoxy, deuterated CM alkoxy.

C haioalkoxy, C cycloalkyl 4 to 6-membered heterocyclyl phenyl,

(a S or 6-memhered heteroaryl containing 1 to 3 heteroaioms each of which i s independently selected from N, 0, and S), -(CM alky lene)~(C.M cycloalkyl},

-(CM alkyieneKphenyl), ~0-(Cs.s cycloalkyl}, -0--(4 to 6-membeted heterocyclyl), -O-phenyl ~0-(C s -s aikyiene)-(phenyl), -0-(C s -3 alk lene)-(C3-s; cycloalkyl),

alkylencMphenyS), -NH-alkyL -MH-haloalkyl, -MM-phenyl, -Nid-eycioalkyl, and -N(alkyl}¾ and the alkyl, alkyiene, eyeloa!kyi, phenyl, heterocyclyl and heteroaryl by themselves or as part of another group, tire each independently substituted with 0 to 3 R'i and R ^iS Is halo, cyaoo, hydroxyl, a ino, Cos alkyl, CM alkoxy, C3-& cycloalkyl, or 4 to 6- emhcred heteroeyel l R * is hydrogen; and.R ^4iJ Is hydrogen.

In any one of the preceding embodiment of Formula (III), IC is CM alkyl,

Cos haioalkyi, CM alkoxy, Cos haioalkoxy. CM cycloalkyl phenyl,

-(Co _? a!kylene)-(Cs.s cycloalkyl), -{CM alkyiene)~(p.henyi); and the alkyl alkyiene, cycloalkyl, phenyl, heterocyclyl, and heteroaryl, by themselves or as part of another group, are each independentl substituted wit 0 to 3 l

In one embodiment of the present invention, the compound is selected from any one of the Examples as described the specification, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof

In one embodiment, the compounds of the present invention have hLPAl ICso values < 5000 nM, using the LPA1 functional antagonist assay; In another embodiment, the compounds of the present invention have hLPAl ICso values < 1000 nM; i another embodiment, the compounds of the present invention ha e hLPAl I€$o values < 500 nM: in another embodiment, the compounds of the present invention have hLPAl ICso values < 200 nM: in another embodiment, the compounds of the present invention have hLPAl 1C _& > values 100 nM; in another embo i ent, the compounds of ihe present invention have hLPA! I(¾ values < SO BM,

II OTHER EMBODIMENTS OP THE INVENTION

I» some embodiments, the compound of Formula (la) or (Ih), or a

pharmaceutically acceptable salt or solvate thereof, is an antagonist of at least one LPA receptor. In some embodiments, the compound of Formula (la) or(Ib), or a

pharmaceutically acceptable salt or solvate thereof is an antagonist of LPA,n In some embodiments the compound of Formula (la) or (Ih), or a pharmaceutically acceptable salt or solvate thereof is an antagonist of LPAg In some embodiments, the compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof is antagonist of LPAv

In some embodiments, presented herein are compounds selected Horn active metabolites, tautomers, pharmaceutically acceptable sabs or solvates of a compound of Formula (la) or (lb).

In another embodiment, the present invention provides a composition comprising at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof

In another embodiment, the present invention pr vides a pharmaceutical composition comprising a phannaceutlcally acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pbamaeeutieally acceptable salt, or a solvate thereof

In another embodiment, the present invention provides a process tor making a compound of the present invention

In another embodiment, the present invention provides an intermediate for making a compoun of the present in veniion.

In another embodiment, the present invention provides a pharmaceutical composition further comprising additional therapeutic agent(s).

In another embodiment the present invention provides a method for the treatment of a condition associated wi th LFA receptor mediated fibrosis comprising administering to a patient in need of snob treatment a therapeutically effective amount of at least one of the compounds of the present invention or a stereoisomer, a tautomer, a pharmaceutically

ί \ acceptable salt, or a solvate thereof As used herein, the term ''patient’ encompasses all mammalian species.

In another embodiment, the present invention pro vides a method of treating a disease disorder, or condition associated with dysreguiation of !ysophosph didic acid receptor 1 (LPAi) m a patient in need thereof, comprising administering a Iherapeuficaily effective amount of a compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof, to the patient. In one

embodiment of the method, tbs disease, disorder, or condi tion is related to pathological fibrosis transplant rejection, cancer, osteoporosis, or inflammatory disorders. in one embodiment of the method, the pathological fibrosi is pulmonary, liver, renal, cardiac, derttal, ocular, or pancreatic fibrosis. In one embodiment of the method, the disease, disorder, of condition is idiopathic pulmonar fibrosis i IPf nonmlcohoiic steatohepaiitls (NASH), non-alcoholic tatty liver disease ( AFLD), chronic kidney: disease, diabetic idney disease, and systemic sclerosis hi one embodiment of the method, the cancer is of the bladder, blood, bone, brain, breast, central nervous system, cervix, colon, endometrium, esophagus, gali bladder, genitalia, genitourinary tract, head, kidney, larynx, liver, lung, muscle tissue, neck, oral or nasal mucosa, ovary, pancreas, prostate, skin, spleen, small intestine, large intestine, stomach, testicle, or thyroid.

In another embodiment, the present invention provides a method of treating fibrosis in a mammal comprising administering a therapeutically effective amount of a compound of the present invention, or a stereoisomer a tautomer, or a pharmaceutically acceptable salt or solvate thereof, to t e mammal In need thereof. In one embodiment of the method, the fibrosis Is idiopathic pulmonary fibrosis (IPF), nonalcoholic

steatohepatiiis (NASH), chronic kidney disease, diabetic kidney disease, and systemic sclerosis,

In another embodiment, the present invention provides a method of treating lung fibrosis (idiopathic pulmonar fibrosis), asthma, chronic obstructive pulmonary disease (COPD), renal fibrosis, acute kidney injury, chronic- kidney disease, liver fi rosis (non alcoholic sieaiohepatitis}, skin fibrosis, fibrosis of the gut, breast cancer, pancreatic cancer, ovarian cancer, prostate cancer, glioblastoma, bone cancer, colon cancer, bowel cancer, head and neck cancer, melanoma, multiple myeloma, chronic lymphocytic leukemia, cancer pain, tumor metastasis, transplant organ rejection, scleroderma, ocular fibrosis, age related macular degeneration (AMD), diabetic retinopathy collagen vascular disease, atherosclerosis, Raynaud's ph nomenon, or neuropathic pain in a am al comprising administering a therapeutically elective amount of a compound of the present invention, or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof to the mammal in need thereof

As used herein,’'treating ¹ or treat ent’' cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) inhibiting the disease-state, l e. , arresting it development; and/or (b) relieving the disease-state, i a , causing regression of the disease state. As used herein, "treating" or "treatment” also include the protective treatment of a disease state to reduce and/or minimise the risk and/or reduction in the risk of recurrence of a disease state by administering to a patient a therapeutically effective amount of at least one of the compounds of the present invention or a or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, or a solvate thereof Patients may be selecte lor such protective therapy based on factors that are known to increase risk of suffering a clinical disease state compared to the general population. For protective treatment, conditions of the clinical disease state mayor may not be presented yet Th protective treatment can be divided Into (a) primary prophylaxis and (b) secondar prophylaxis. Primary prophy laxis is defined as treatment to reduce or minimize the risk of a disease state in a patient that has not yet presented with a clinical disease state, whereas secondary prophylaxis is defined as minimizing or reducing the risk of a recurrence or second occurrence of the same or similar clinical disease slate.

The present invention may be embodied In other specific forms without departing from the spirit or essential atributes t ereof This invention encompasses all

combinations of preferred aspects of the Invention noted herein . It Is understood that any and all embodiments of the prewm irs ention may be taken In conjunction with any other embodiment or rmibodknents to describe additional embodiments.. It Is also to be understood that each individual element of the embodiments Is its own independent embodiment. Furthermore any element of an embodiment is meant to be combined with any and all other dements front any embodiment to describe an additional embodiment. III. CHEMISTRY

Throughout the specification and Hie appended chu s, a given chemical formula or name shall encompass all stereo sod optical isomers and racemates: thereof where such isomers exist. (Mess otherwise indicated, all chiral (enantiomeric a&d diasiereomsric) and racemic forms are within the scope of the invention. Many geometric isomers of C>€ double bonds, ON double bonds _» ring systems, and the like can also be present in the compounds, and all such stable i somers are contemplated in the present in ven ti on. Cis~ iil imm- (or IE and 2~) geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of Isomers or as separated isomeric forms. The present compounds can be isolated in optically active or racemic forms. Optically active forms may he prepared by resolution of racemic forms or by synthesis Eons optically acti ve starting materials. All processes used to prepare compounds of the present invention and intermediates made therein arc considered to be part of the present invention. When enantiomeric or diasiereomerie products are prepared, they may he separate by conventional methods, for example, by chromatography or fractional crysiailiMion Depending on the process conditions the end products of the resent invention are obtained either in free (neutral) o salt form. Both the free form and the salts of these end products are within the scope of the invention. If so desired, one form of a compound may b converted into another form. A free base or aci may he converted info a salt; a salt may be converted Into the free compound or another wit; a mixture of isomeric compounds of the present invention may be separated into the individual isomers. Compounds of the present in vention, tree form and salts thereof, may exist in multiple tautomeric forms, in which hydrogen atoms ar transposed to other parts of the molecules and the chemical bonds bet ween the atoms of the molecules are consequently rearranged. It should be understood that all tautomeric forms, insofar as they may exist, are included within the invention.

The ter "stereoisomer" refers to isomers of identical constitutkm that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror Images of each o ther and are not superimposable. The term "diastereomer'" refers to stereoisomers that are not mirror images.. The term "racemate" or ^' Tacemie mixture"

1.8 refers to a composit on composed of equimolar quantities of two enanfiomerie species, wherein the composition is devoid of optical activity,

The symbols "II” and "S" represent the configuration of substituents around a chiral carbon aimnfs). The isomeric descriptors ^! ¾" *§ ^* · are used as described herein for indicating atom configurations) relative to a core molecule and are intended to be used a defined in the literature (IUPAC Recommendations 199(\ Pure and Applied Chemistr _s 68:2193-2222 (1996))

T¾e ter "ehlm!" refers to the structural characteristic of a niolecule that makes it impossible to superimpose it on its mirror image. The term ^" homochiral" refers to a state of enantiomeric purity The term "optical activity" refers to the degree to which a Iiomodiirai molecule or nonracemic mixture of chiral molecules rotates a plane of polarized light

As used herein, the term "alkyl” or "aikylene” is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups havi ng the specified number of carbon atoms. Whi le ¾&nG denotes a monovalent saturated aliphatic radical (such as ethyl),“a!fcy!epe” denotes a bivalent saturated aliphatic radical (such as ethylene). For example,”C \ to ^{( :} K _? alky!” or alky!” is Intended to include Cp Cy, groups. "C _s to C aikylene” or "Cm a aikylene”, I intended to include€¾ CA, C3,€4, C¾, (¾,€ ₇ , Cg,€9, and C aikylene groups. Additionally, for example, "Cy to C¾ alkyl" o alkyl" denotes alkyl having 1 to 6 carbon atoms; and”€ _j or "C^ aikylene" denotes aikylene having 1 to 6 carbon atoms; and "€) to C4 alkyl" or "Cg ₄ alkyl” denotes alkyl having 1 to 4 carbon atoms; and "C; to€ ₄ aikylene” or aikylene" denotes aikylene having 1 to 4 carbon atoms. Alkyl group can be unsubsiituied or substituted with at least one hydrogen being replaced by another chemical group. Example alkyl groups include, but are not limited to, methyl (Me), ethyl (Bi), propyl (e,g. , n-propyl and isopropyl), butyl (e.,g , n-butyi isobutyl, /-butyl), and pentyl (e.g , n-pentyl, isopentyl, neopentyl). When "(¾ alkyl" or "{¾ aikylene" is used, it is intended to denote a direct bond. Furthermore, the term“alkyl”, by itself or as part of another group, such as alkyla nioo, haloalkyl, hydroxyalkyi, aminoalkyl, alkoxy, alkoxyalkyl, haloaikoxyalkyl, and haloalkoxy, can be an alkyl having 1 to 4 carbon atoms, or 1 to 6 carbon atoms, or 1 to 10 carbon atoms. l-feferoaikyl" refers to an alkyl group where one o more carbon atoms have been replaced with a heteroatom, such as, C), M _> or S. For example. If the carbon atom of the alkyl group which is attached: to the parent molecule is replaced with a heteroatom (¾g. , O, fe, or S) the resulting hcferoalkyl gnsups are, respectively, an alkoxy group (wg , ~OC!¾, etc,), an alkylainino (g , -N1|C¾ - (€¾) _¾ etc.), or a thioalkyl grou (e.g. , -SC¾) if a non- terminal carbon atom of the alkyl group which i not attached to the parent mol eeuie is replace wife s heteroatom (e.g , O, fe, or S) and the resulting heieroalkyl groups are, respectively, an alkyl ether (e,g , -CFbCHr-O-Gfe, etc ), an fek kminoalkyl

(e.g. , -CH2 HCH3, -C¾N(Cffi} _¾ etc ), or a thioalkyl ether tug. ,-Q¾-S-€Fb). if a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g , O, N, or S), the resulting heteroalkyl groups am, respectively, a hydroxyaJk l group (e.g., ~C¾Q¾~OH) an aruinoalkyl group (eg -G-fiNBy), or an alkyl thiol group (e.g., -ClBCFb-SB). A hcferoalkyl group can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms, A Ci-Cs heieroalkyl group means a hcferoalkyl group having 1 to 6 carbon atoms,

"Alkenyl* or "alkenytene" is intended to include hydrocarbon chains of either straight or branched configuration having the specified nu ber of carbon at s and one or more, preferably one to two, carbon-carbon double bonds that may occur in any stable point along the chain. For example, "Ca to€4 alkenyl" or”C,u; alkenyl” (or alkeaylcne), is intended to include€2 _* €3, C C s, and Cfi alkenyl groups. Examples of alkenyl include, but are not limited to, ethenyk i-propenyl, 2-propenyl, 2-butenyl, 3-butenyfi 2-pentenyl, 3-penteayt, 4-pentenyk 2~hexe»yL 3-bexenyL 4-hexen L 5-hexenyl, 2-methyl~2~ propenyl, and 4-methyl-3-pentenyi

"Aikynyl" or’’alkynykne” is Intended to include hydrocarbon chains of either straight or branched configuration havin one or more, preferably one to three, carbon- carbon triple bonds that may occur in any stable point along the chain. For example, "fib to Cs alkyuyF or "Cfes alkyny!" (or alkyuylene), is intended to include€2, C¾, Gs,€¾, and Cs alkyuyl groups; such as ethyuyi propynyk butyny!, pentyayi and bexynyh

As used herein,“aryl&ikyF (a.k.a. aralkyl),“heteroarylalk)·; ^" "cajbocyclylalkyr or ^s ¾eteroeyelyialkyP refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp ^J carbon atom. Is replace with aa aryl, heteroaryl, eurhocycly], or lietcrocyclyi radical, respectively. Typical arylaikyl groups Include, but are not limited to, benzyl, 2-phsnyfeihan~i~yk naphthylmethyi 2- aaphthyiethaoH~yk naphthobemxyi, 2~naphthophenykthan l -yl and the like. The arylalky!, heteroarylallyl., eafbocyclyMky!, of hefetocyclylalkyl group can comprise 4 to 20 carbon atoms and 0 to 5 heteroatoms, e-g. , the alkyl moiety may contain 1 to 6 carbon

5 atoms.

The term "benzyl", as used herein, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally he substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OC¾,€h F, Br, I, CO. H0 ₂ , Kl¾, N(C%}& N(CI%) ₂ , Cry, OCP ₃ , C(-0)CH _¾ , SC% S(*?0}CB _3s SH¾ ₂ a¾,

10 CH _S , CH _j CFiy, CCfeH, and C<¾P% “Benzyl” can also be represented by formula“Bn

The term "alkoxy" or "alkyipxy*' refers to an ~C>a1kyl group.“Cs to C _& aikoxy" or "C u alkoxy” (or alkyloxy), is intended to include€ _¾ i¾ (¾, (Fs. Cs, and Cs aikox groups. Example aikoxy groups Include, but are not limited to, eihoxy, ethoxy, propoxy (wy,, mpropoxy and isopropoxy), and O-butoxy. Similarly, "alkylihio" or“ihioaikoxy"

15 represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge; for example, methy!-S- and eihyi~S~

The term“a!kanoyfe or“alkyicarhonyf as used herein alone or as part of ano ther group refers to alkyl linked to a carbonyl group. For example, alkylcarbonyl may be fepresented by alkyf-C(O)-. "C _j to€¾ alkyiearbonyl" (or alkylcarbonyi), is Intended to

20 include€ _s , (¾,€¾. Cfi, C5, and C _§ alkyI C(0)~ groups.

The term‘felkyisulibnyf ^; or“sulfonamide” as used herein alone or as part of another group refers to alkyl or amino linked to a su!fonyl group. For example, alky isul fun i may be represented by ~S(OpR.\ while sulfonamide .may be represented by ~S((>}2NR ^e R ^d . R’ is€ _| to C _§ alkyl; and 1C and R. ^s are the same as defined below for 5 “amino ^” .

The term“carbamate” as used herein alone or as part of another group refers to oxygen linked to an amido group. For example, carbamate may be represented by N(R¾ ^i! )--C((}}-0~ _::; and R ^c and R ^d are the same as defined below for“aminoC

The ter “a ido ⁵⁴ as used herein alone or as part of another group refers to amino

30 linke to a carbonyl group. For example, amido may be represented by M(R¾fe~C(0}-, an R ^c and R ^d are the same as defined below for“amino ⁵ /. The fen»“am o” is defined as -NR ^¾ R:fr wherein R ^c; and R ^c2 are independently H or€ i:- ₆ alkyl; or alternatively, R ^si a d R. ^ci , takes together with the atoms to which they are attached, form a 3~ to S-menibered heterocyclic ring which Is optionally substituted with one or more group selected from Mo, cyano, hydroxyl, amino, cxo, Cro alkyl, alkox> , and ammo kyl When E ^ci or R* ² (or both of them) is Cog alkyl, the amino group can also be referred to as a!kydarnino. Examples of alkyfemino groupinclude, without limitation, methyfamino, eihyi&mino, propyiamino. isopropylamino and the like. In one embodiment, amino is -NHa.

The term“aminoalkyF' refers to an alkyl gro up on which one of the hydrogen atoms is replaced by an amino group, For example, aminoalkyl may be represented by N(R¾ ^t )~alkyfene~. ^t¾ C; to C _$ ' or annnoalkyr' (or aminoalkyl), is intended to inclnde C), C¾, (¾, C ₄ , (¾, and Cg aminoalkyl groups.

The term“halogen” or '¾alo’\as used herein alone or as part of another group refers to chlorine bromine, fluorine, and iodine, with chlorine or fluorine being preferred.

"Fiaioalkyi" is Intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups ban tug the specified uumher of carbon atoms, substituted with one or more halogens ⁿ C to C¾ haioalkyF' or ⁿ C _f ^ halqalkyF (or haioalkyl), is intended to include€), C¾, (¾, C ₄ ,€5, an €¾ haioalkyl groups. Examples of haioalkyl include, but are not limited to, finoromediyl, diiluoromefeyL ini!uoiomethyk

tnchloromethyf, peniaflnoroethyi pentachioroethyl 2,2.2~triflnoroothyl,

fepiailuoropropyl, and heptachl oropropyl. Exam ples of haioalkyl also include

"fiuosoalkyi” that is intended to Include both branched and straight-chain saturated ali hatic hydrocarbon groups having the specified number of carbon atoms, substituted with I or more fluorine atoms. The term“poiyhaloalkyf ⁵ as used herein refers to an felkyf group as defined above which includes fro 2 to 9, preferably from 2 to 5, halo substi uents, such as F or Cl, preferably F, such as polyfluoroalkyb for example, CFsCHe, CFj or CFsCFfeWb.

'Tlaloalkoxy* ¹ or ^: haIoalkyioxy“ represents a haioalkyl group as defined above with the indicated numbe of carbon atoms attached through an oxygen bridge. For example, Mended to uiciade G^, C ₂₅ C _3, G4,€5, and Cg haloal.koxy groups. Examples of haloalkoxy inclnde, but are not limited to, irifinoromethoxy, 2 2 il uoroethoxy, and pejUnfinorothoxy. Similarly, "halo ylthk*’ or "thiohaloalfcoxy” represents a haloalkyi group as defined above with the indicated number of carbon atoms attached thro ugh a sulphur bridge; for example trifiuoromethyfiS-·, and penialfeoroeihyl-S;-. The ter ‘apolyhaloalkyloxy ^* a used he ein refers to as ^alkox ⁵ ' o folk loxy'- group as defined above which includes from 2 to 9, preferabl from 2 to 5, halo substituems. such as F or Cl, preferably F, such as poiyfliioroalkoxy, for example, Cl¾C tO ₅ CFsO or CF3CF2CH2O,

"Hychoxya!kyr is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups havin the specified number of carbon atoms, substituted with 1 or more hydroxyl (OH). "C* to ¾ hydroxyalkyF (or hydroxyalky!}, is intended to include Eh , <¾, Cy€4, CO, and C^ hydroxyailcyl groups.

The term "cyeloalkyi” refers to eyelized alkyl groups, including rooKO-, bi~ or poly-cyclic ring systems;”t¾ to C¾ cycioalkyl" or "C3 cyefoaikyF' is nten e to indbde C¾€¾, C _$ , C¾, C? and C« cyeloalkyi groups, including monocyclic, bicyclio, and polycyclic rings Example cyeloalkyi groups include, but are not limited to, cycfopropy L cyclobutyl, cyetepeulyl, eyclohexyl, and norbornyl Branched cyeloalkyi groups such as l -uxothyieyelop pyl and -methylcyeiopropyl and spiro and bridged cycloalkyl groups are included in the definition of '‘cyeloalkyi”.

The term "eycloheteroaikyl" refers to e clized heietoalkyl groups, including mono-, bi~ or poly-i-ydk ring systems.’’€3 to C? cycloheteroalkyi" or ⁿ C^

eydoheteroa! k.y G is unended to include <V Cfo and C7 cycloheteroalkyi groups. Example cyeloheleroalkyl groups Include, but ate not limited to, oxeiauyl

tetrabydro&ranyl, telr hydropyranyL axclidinyl, pyrrolidinyl, plperidinyl, morpholinyk and piperazinyL Branched cyeloheteroalkyl groups, such as piperidiny!methy 1, piperazinylmethyl, morpholmylmethyl, pyrid yhneihyl, pyridizy netb l,

pyrimldylmethyL and pyraxmyknethyl, are included in the definition of

"cycfoheteroalkyr.

As used herein, "carbocycleT’toarbocydyl’ ¹ or "earbocyciic residue" is intende to mean any stable 3~, 4-, 5-, 6~, 7-, or ffimembensd monocyclic or bicyclic or ?~, 9-, 10-,

11-, 12-, or 1 unnumbered bicyclic or tricyclic hydrocarbon ring, any of which may be saturated, partially unsaturated, unsaiotaied or aromatic. Examples of such carboeycles include, hut are not limited to, cyelopropyl, cydobutyi, cyeiobuiehyl, eyciopentyi, eyeiopentenyl, eyclohexyl, cydohepieny!, eydoheptyl, cye!ohepienyl, adamantyl cyefoocty cyeiooctenyl cyelooetadienyl [3 3 {S]hieyefooctane, [4,3.0]hicyeiotmnane, [4 4 01bicyelodecane (decaii») _f |2 2.2Jbicyeiooeiane, iluorenyl, phenyl, naphthyl, mdanyl, adamantyl, anferacenyl, anti tetrahydronaphthyl (tebuhn} As sho n above, bridged rings are lso iueiuded in the definition of eatboeyele (kg., [2.2.2]hicyelooctane) Preferred 5 earkoeycles, unless otherwise specified, are cyelopropyl, cycldbutyl, cyelopentyl,

cyolohexyl, phenyl and indanyl When the term fearboeyciyi" is used, it is intended to include "aryl", A bridged ring occurs when one or more carbon atoms link two non- adjacent carbon atoms Preferred bridges are one or two carbon atoms. It is noted that a bridge al ways converts a monocyclic ring into a tricyclic ring- When a ring is bridged, the 0 substituents recited for the ring may al so be presen t on the bridge.

Furthermore, the term foarbocydyr, indudlng feycloaiiyl” and feycloaikenyFy as employed herein alone or as part of another group includes saturated or partially unsatorafod (containing 1: or 2 double bonds) cyclic hydrocarbon groups eotdamlng to 3 rings, including monoeyeliealkyi bkydleaikyl and irkydkalkyi, containing a total of 3:5 to 20 carbons forming fee rings, preferably 3 to 10 carbons or 3 to 6 carbons, forming the ring and which may be fused to 1 or 2 aromatic rings as described for aryi, winch include eyclopropyl, cyelobutyL eyclopeniyl cyclohexyl eycioheptyl, cydooctyl eydodecyl and cydododecyl eydohexenyl.

0 any of which groups ma be optionally substituted with 1 to 4 substituents such as

halogen, alkyl, alkoxy, hydroxy, aryl, ary!oxy, arylalkyl, cycloalkyl alky!&mido, aikanoylaroioo, oxo, acyl, arylcarhonylamino, nitre, cyano, thiol and/or alkylthio and/or any of the alkyl substituents.

As used herein, the term "bicyclic carbocyelyi" or "bicyclic earboeydk group" is5 intended to mean a stable 9- or IG-me bered carbocyclic ring system that contains two fused rings and consists of carbon atoms. Of the two fused rings, one ring is a benao ring fused to a second ring and me second ring is a 5- or 6-membered carbon ring which is saturated, partially unsamrated, or unsaturated. The bicyclic carbocychc group ma he attached to its pendant group at: an carbon atom which results m. a stable structure. Hie0 bicyclic carbocychc group described herein may be substituted on any carbon if the resulting compound is stable. Exa ples of a bicychc earbocyelic group are, but not limited to, naphthyl, fWdihydronaphthyl I ,2,3 _; 4--ietrahydronaph†hyl and indanyi

As used herein, the term "arylfe as employed herein alone or as pari of another group, refers to monocyclic o polycyclic (including bicyelie and tricyclic) aromatic hydrocarbons, including, for example, phenyl, naphthyl, anihraeeoyl, and phenanthranyL Aryl moieties are well known and described, for example, in Lewis, K.J., ed,, Mawkys Conde sed Chemical Dictionary, 1 th Edition, John Wiley & Sons, Inc·,, New York (1997). In one embodiment, the term“aryl ^* denotes monocyclic and bicycle aromatic groups containing 6 to 10 carbons In the ring portion (such as phenyl or naphthyl including 1 -naphthyl and 2-naphthyl). For example, "C _g or€*¾ aryl" ^' or

refers to phenyl and naphthyl Unless otherwise specified, "aryU, "C% erC _j p aryl)

"Cg..i f _} aryl", or "aromatic residue” may he imsnbstituted or substituted with 1 to 5 groups, preferably to 3 groups, selected from -OH, -Cl, -F, ~Br, -I, -CM,

-N0 ₂ , -N% -N(CH ₃ }¾ ~N(CI¾, -CF ₃ , ~0CP ₃ , -C(0)CH ₃ , -SCH ₃ , ~S<0)CH ₃ , -S(0) ₂ CB ₃ , ~CH ₃ , -C%CH ₃ , -€0 ₂ i l. and -COaCHy,

The term“benzyl", as. used heroi n, refers to a methyl group on which one of the hydrogen atoms is replaced by a phenyl group, wherein said phenyl group may optionally be substituted with 1 to 5 groups, preferably 1 to 3 groups, OH, OC%, Cl, F, B , I, CN, N€h, NH¾ K(<¾)H, NiCH fe, CP ₃ , OGIfo C(====0)CI¾, SC¾, SfoO)CI¾, S(<%C1¾, €¾, C¾C¾, COW. and CQzCHs.

As use herein, the term "heterocycle", "heterocycl i", or "heterocyclic group** is intended to mean a stable 3-, 4-, 5-, 6~, or 7-membefed monocyclic or 5-, o··, 7~, 8-, 9~,

10-, 1 1 -, 12-, 13-, or 14~membered polycyclic (including bicyelie and tricyclic) heterocyclic ring that is saturated, or partially misaturated, and that contains carbon atoms and L 2, 3 or 4 heteroatoms independently selected from N, O and S; and including any polycyclic grou in. which any of the above-defined heterocyclic rings is fused to a carhocyelrc or an aryl (e,g., benzene) ring. That is, the term "heterocycle”,

"heterocyelyiT or’’heterocyclic, group" includes non-aromatic ring systems, such as heterocycloalkyl and heteroeyeloalkenyl. The nitrogen and sulfur heteroatoms may optionally fee oxidized (f a, \$®0 and S(0) _|3, wherein p is 0, 1 or 2). The nitrogen atom may be substituted or unsubstituted (f a , N or MR wherein R is H or another substituent, if defined). The heterocyclic ring may be attached to its pendant group at an heteroaiom or carbon atom that results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen tom if the resulting compound is stable. A nitrogen in the heteroeyele ay optionally be quatermned. It is preferred that when the iota! number of S and 0 atoms in the heterocycle exceeds I , then these hetsroatoms arc not adjacent to one another, it is preferred that the total number of S and 0 atoms in the heteroeyele is not o than L Examples of hetercyelyl include _s without limitation, aeeddinyL piperazinyl piperidinyl. piperldonyl, piperonyi, pyranyl, morpltolinyi tetrabydro&ranyl, ieirahydroisoqninolinyh teirahydroquinoliuyt, morpholinyi, dibydroferoP ~h j t rahydrofeatL

As used herein, the tenn "Mcyelic heteroeyele" or "bi cyclic heterocyclic group" 1s intended to moan a stable 9- or lik nembered heterocyclic ring system which contains two fused rings and consists of carbon atoms aid L 2, 3, or 4 heteroatoms Independently selected f om N, O and S. Of the two fused rings, one ring is a 5- or b-memhered nionoeydfe aromatic ring comprising 5-membered heieroary! ring, a 6-membered heteroaryl ring or a benzo ring, each feed to a second ring. The second ring is a 5- or to embered monocyclic ring which is saturated, partially nnsaturated, or imsaturated, and comprises a 5 mwmbered heteroeyele, a 6-menibered heteroeyele or earboeycle (provided fee first ring is not benxo when the second ring is a earboeycle)

The bicydic heterocyclic group may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The bicyoho heterocyclic group described herein may be substituted on carbon or on. a nitrogen atom if the resulting compound Is stable. It is preferred that when the total number of S ana O atoms in the heteroeyele exceeds I , then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroeyele is not more than 1. Examples of a bicydic heterocyclic gro up are, but not limited to,

L2,3,4detrahydroqumohuyL l ,2,3,4rietrahydroisoquinolinyh

5,6,7, 8-tetrahydro-quinoiinyL 2,3feihydro-benzofnrany!, chroroanyl,

1 ,2,3,4-ietrahydro-qulnoxahnyh and 1 ,2,3,4-tetrabydro _“ qninazoIinyi

Bridged rings are also included in the definition of heteroeyele A bridged ring occurs when one or more atoms dm , C, O, N, or S) link two non-adjacent carbon or nitrogen atoms. Examples of bridged rings Include, hut are not limited to, one carbon atom, two carbon atones, one nitroge atom, two nitrogen atoms, and a carbon -nitrogen group. It is noted that a bridge always converts a monocyclic ring into a tricyclic ring. When a ring is bridged, the substituents recited for the ring may also be present on the

As used herein., the term "heteroaryl” is intended to ean stable monocyclic and polycyclic (including bicyclic and tricyclic) aromatic hydrocarbons that include at least one heteroatom ring member such as sulfur, oxygen, or nitrogen Beteroaryi groups include, without limitation, pyridyl, pyriroldinyl, pyrazirryi pyridaxlnyl, triazmyl, fury!, qainoJyl, isoquino!yi, thienyl, imkteolyl, thioxolyh indolyi, pyrroyi oxazolyl, benzofuryl, benxothienyl, bsnzthiazohi, isoxazoiyl, pyrazolyl, triagolyi, tetrazolyl indaxo!yl, 1 ₅ 2,4~thiadiazoM _s isothiazolyl, puriuy!. carbazolyf, benzlmidazoIyL insMinyi beuxodioxolanyL and bpnzpdioxane. Heteroaryl groups are s«bstiiuied or irosubstituted. The nitrogen atom is substituted or irosubstituted (Le. , hi or NR wherein R is H or another substituent., if defined). The nitrogen and sulfur heteroatoms may optionall be oxidized (ie,, N- 0 and S(0)p _s wherein p is 0, 1 or 2)

Examples of heteroaryl also Include, but are not limited to, acridinyh axocinyl benximidaxotyl, beozoforanyl, benxothloihranyi, benzoihiophenyi benzoxazolyi, benxoxazolmyl, beuxtblazoM, heuxhiaxolyl, benxtetrazoiyl henzisoxazolyl,

henxisolhiaxo!yL benzimidaxolinyl, earbazolyl, 4aH~carbazo3yl, carholinvi chroniaoyL ehromenyi, cirmoimyL decahyd.roquinofinyi 2 /,d/ i _J S,2-dithiazmyl _> iuranyl, finaxanyl, imidaxoiidinyh Imidaxolinyl, imidazo!yl, ilidndazolyl, iroMaxolopytkiinyl, mdoleoyL mdohnyb mdoiixiuyl , indolyl. 3H-indolyl, isatinoyl, isobenzoihranyl, isochromanyl, isolndazo!yi isomdolinyi, isoindoly!, isoquiuoimyl, isothia lyl, isothlazolopyridinyi, isoxazoiyl, isoxazolopyrldinyi, methylenedioxyphenyl, napbthyridinyi,

oetahydroisoqu oli uyl, oxadlazoiyi, .! ₅ 2,3~oxadiaxo!yi, 1 ,2,4~oxadlaxoly!,

1 ,2,5-oxadiazolyi _« 1 ,3.4-oxadIaxolyL oxazolidinyl, oxazolyl, oxazolopyrldroyi, oxazolidinylp rl ldin i. oxmdo!yl, pyrimidlnyl, phenanihridin l, phenauiiiroliuyL phenazinyL plienotbiazinyl phenoxathianyl, phenoxazinyl phthalaxinyL pteridiuyl, purinyi, pyrazinyl, pyrazolidirryl, pyraxolinyL pytazolopyrid royL pyrazolyl, pyridazinyL pyridooxazolyL pyridoimsidazoiyl, pyridoiliiaxolyi, pyridinyl, pyrimidmyL pyrrolidiuyl pyrrolinyi, 2-qwrroli dorsy 1 , 2B~pyrro lyl, pyrrolyi qumazofiuyl, quinoiinyi

4/frt _j u oimnyi, q uoxalinyl, quimtclidinyl, tetrazolyl, teirahydroiuranyi

(etrahyJroisoquinolinyi, tetrahydroqidoolinyL hHN,2,S~ihiadiazmyL L2 ₅ 34hiadiazoM, L2,4frhiadiazolyl, l,2,$dhladiazol l l,3,44hiadiaxoiyL thlsnthmayl thiazolyi thienyl, ibiazdlopyridhiyl tliienothiazolyi, thieramxazolyl thtenoi idaxoiyj, tMophenyl, triazinyl,l ,2,3~trlazo1yI, !,2,4~triaxolyi, l,2,5~tria¾oiyL 13,4~triaxolyl nd xaoihenyL

Examples of 5- to lO-membered heteroaryl include, but are not limited to, pyridinyk fhranyl, thienyl pyrazoiy!, Imidaxolyl, Imidaxolidinyl indoiyl, teirazoM, isoxazoiyl oxazolyl, oxadlazotyl, oxazolidmyl, thladiazinyl thiadiazoiyL tMazolyl, triazmyl, triazo!yl benzimi azolyl 1 f/rindaxolyl, benzofrmmyk henxoihio&ranyl, benxietrazolyl, benzotrkzolyl, benxisoxaxolyi, bem xnxotyl oxlndolyl, benzoxazolinyl, beMdhiBxolyl benziselMaxolyl iaatinoyL isnqyinolinyl, oetahydrolsoqninolinyl, isoxaxolopyridioyl quinazolinyt qumohnyl, isoihiazolopyridmyl tbiazolopyridinyl oxazofopyridinyl, imidazolopyrid yl, and pyTaxoiopyridinyl Examples of 5- to

6-membered heieroaryf include, but are not limited to, pyridinyl foraayi thienyl, pyrroiyL pyrazolyl, pyraxinyl imidaxoly! imidaaoiidlnyt, indoiyl tetrazolyl, IsoxazoM, oxazolyl oxadiaxolyh oxazolidinyl thiadiaxlnyl, th diszo!yl, thiazolyl, triazinyl and triazoly! In some embodiments, the heteroaryl are selected from benxthiazp!yl, inudaxoipvtidmyi pyrrolopyridlnyl q no!inyl and mdolyi.

Unless otherwise Indicated, "earboeyelyU or ^feeterobyelyf ^* Includes one to three additional rings fused to the carboeyclie ring or the heterocyclic ring (such as aryl, cycfoa!kyl, heteroaryl or cycloheteroalkyi rings), for example,

and ma be optionally substitnied through available carbon or nitrogen atoms (as applicable) with 1, 2, or 3 groups selected from hydrogen, halo, haioalkyi, alkyl, haioalkyi, a!koxy, I loalkoxy, alkenyl trliinororneihyl, tritluoromethoxy, alkynyl, cycloalkykalkyl, ey oheteroa!kyl, cycloheteroalkylalkyl aryl, heteroaryl aryialkyl, aryioxy, aryloxyalkyl, arylalkox , alkoxycarbtmy 1 , aryl carbonyl , aryialkeny ! ,

amraoearbonyiaryl, aryilino, arylsulfinyl arykxo, heteroarylaik l freteroary laikenyl heieroarylbeferoaryl hefcrasryloxy, hydroxy, nitro, cyano, thiol, uikylthio, arylihio, heteroaryithio, avyfihloatkyk alkoxyarylthio, alkylcarhonyk srylearhooyl

aikylaminoearbonyl aryiaminoearbonyi, alkoxycarbonyl aniinoearbon l,

alkyiearbony!oxy, arykarbon ioxy, aiky!carbonyla ino, arykarboyi amino, aryisulfiuyl arylsulfinyialkyi, arylsulfonyla iao and ary Isuiibnatnihocarbonyl and/or an of the alkyl substituents set out herein.

When any of the terms alkyl, alkenyl alkynyi cyelo&lkyi, carbocydyl, heteroeye!yi aryl, and heteroaryl are used as part of another group, the number of ear bon atoms and ring members are the same a those defined in the terms by themselves. For example, a!koxy, haioalkoxy, alkytem o, halcaikyL h droxya!kyt ammoalkyl haioalkoxy, aikoxya!koxy, haloalkylamino, alkoxyalkyfamino, haloalknxyalkylamino, alkyltbio, and the like each independently contains the number of carbon atoms which are the same as defined for the term“alkyl ⁵ , sueh ax 1 to 4 carbon atoms, I to 6 carbon atoms, 1 to 10 carbon atoms, etc. Similarly, eyeioaJkoxy, hetemcydyioxy,

cycloalkyiannno, heterocydylammo, araikylamino, arylamlno, aryloxy, aralkyloxy, heteroaryloxy, hcteroaryla!kyioxy, and the like each indepdenily contains ring members which are the same as efi ed for the terms 'kycloalkyl ⁵ ,“heteroeyclyp,“aryll and “heteroatyF, such as 3 to 6-memhered, 4 to 7-membered, 6 to 10-membered, 5 to 10~ memhered, 5 or b-niembered, etc.

In accordance with a convention used in the art, a bond pointing to a bold line, y" ^'

such as as used in structural formulas herem, depicts the bon that is the point ot attachment of the moiety or substituent to the core or backbone structure.

In accordance with a convention used in the art a wavy or squiggly bond In a structural formula, such as , is used to depict a stereogenie center of the carbon atom to which Xy Y ^? , and Z ⁵ arc attached and is intended to represent both enantiomers in a single figure. That is, a structural formula with such as wavy bon denotes each of the enantiomers individually, such as as well as a racemic mixture thereof When a wavy or squiggly bon is attached to a double bond (such as i>€ or C~N) moiety, it Include ci$~ or tram- (or if- and Z-) geometric isomers or a mixture thereof 0 It is understood herein that if a earbocyeiic or heterocyclic moiety may be bonded or otherwise attached to a designated substrate through differing zing atoms without denoting a specific point of atachment., then ail possible points are intended, whether through a carbon atom or, tor example, a triya!ent nitrogen atom. For example, the term 5 ‘foyridyfi" means 2-, 3- or 4-pyrk!yk the term“thiehyP means ^; 2~ or 3-thienyl, and so forth.

When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, the such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom in. which such substituent is bonded to the rest of the:0 compound of a given formula, then such substituent may he beaded via any atom in such substituent Combinations of substituents and/o variables are permissible only if such combination result in stable compounds.

One skilled In the art will recognize that substituents and other moieties of the compounds of the present invention should be selected in order to provide a compound5 which is sufficiently stable to provide a pharmaceutically useful compound which can be fomufiaied into an acceptably stable pharmaceutical composition. Compounds of the present Invention which have such stability are contemplated as felling within the scope of the present invention

The term "counter ion" is used to represent a negatively charged species such as0 chloride, bromide hydroxide, acetate, and sulfide. The term foneta! ton" refers to alkali metal ions such as sodium, potassium or lithium an alkaline earth metal ions snob as magnesium and c lciu -w wml as zinc and aluminum.

As referred to herein, the term“substituted" meats that at least one hydrogen atom (attached to carbon atom or heieroatom) is replaced with a non-hydrogen group, provided5 that normal valencies are maintained and that the substitution results in a stable

compound. When a substituent is oxo (ie., ^::: 0), then 2 hydrogens on the atom are replaced. Oxo substituents are not present on aromatic moieties. When a ring system (e _> , earbocyeiic or heterocyclic) is said to be substunted with a carbonyl group or a doable bond, it is intended that the carbonyl group or double bond be part (Le., within) of0 the ring. Ring double bonds, as used herein, are double bonds that are formed between two adjacent ring atoms (c.g , i>€, C> ^: N, or The term ^w substituted ^,> in reference to alkyl, ey oalkyl, heteroalky.1, cycloheteroaikyl, alky!ene, aryl, ary!a!ky!, heteroaryl heieroarylaikyl, carhoeyclyl, and hetorocyclyl, means alkyl cycloalkyl, heteroalkyl, eycloheternalfcyL alkyiene, aryl arylalkyl heiero&ryl, heteroaryialkyl, carbocyclyl, a i heterocyelyf, respectively, m which one or more hydrogen atoms _* which are attached to either carbon or heteruatom, are each independently replaced with one or more non- hydrogen suhstituetd(s).

In eases wherein there are nitrogen atoms (ag. , amines) on compo unds of the present invention, these may he converted to N-oxides b treatment with an oxidizing agent (e.g;, mCPBA and/or hydrogen peroxides) to afford other compounds of this invention. Thus, shown an claimed nitrogen atoms are considered to cover both the shown nitrogen and its N -oxide (lSi-~ Q) derivative.

When any variable occurs more than one time in any constituent or formula for a compound its definition at each occurrence is independent of its definition at every other occurrence. Thus _* for example if a group is shown to be substituted with if 1 , 2, or 3 R groups, then said grou be imsubsdtirted when it is substituted with 0 R group, or be substituted with up to three R groups, and a each occurrence R is selected Independently from the deimibon of R.

Also, combinations of substituents and/or variables are permissible only if such combination result in stable compounds.

As used herein, the term ⁴ tautomer refers to each of two or more isomers of a compound that exist together in equilibrium, and are readily interchanged by migration of an aa.-m or group within the molecule For example, one skilled in the art would readily understand that a J-iriazole exists in two tautomeric forms as defin d above:

Thus, this disclosure is intended to cover all possible tautomers even when a structure depicts only one of them.

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, and/or other problem or complication, commensurate wife a reasonable benefit/risk ratio.

] The co pounds of the present invention can be present s salts, which are also within the scope of this invention Pharmacei cally acceptable salts are preferred. As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof The: pharmaceutically acceptable salts piths resent invention can he symhesixed .from the parent compound that contains a basic or acidic moiety by conventional chemical methods:. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric: amount of the appropriate base or acid in water or In an organic solvent, or in a mixture of the two; generally, nonaqueoos media like ether, ethyl acetate, ethanol isopropanol, or acetonitrile are preferred. lists of suitabl salts are found in Remington's Pharmaceutical Sciences _s 1 i Edition, Mack Publishing Company, Easton, PA (1990), the disclosure of which is hereby incorporated by reference.

If the compounds of the present invention have, for example, at feast one haste center, the can form acid addition salts. These are formed, for example, with strong inorganic adds, sued as mineral acids, for example sulfuric acid, phosphoric acid or a hydrohallc acid, with organic carboxylic acids, such as alkaneearboxyiic acid of 1 to 4 carbon atoms, for example acetic acid, which are unsnbstitated or substituted, for example, by halogen as ehloroaeedc add, such as saturated or i saforaled dicarboxyiic acids, for example oxalic, maionic, succinic, maleic, fumaric, phthabc or icrephthalie acid, such us bydtoxycatboxylie acids, for example ascorbic., glycolic, lactic, malic, tartaric or citric acid, such as amino acids, (for example aspartic or glutamic a d or lysine or arginine), or benxolc add, or with organic sulfonic acids, such as (C -Cfi) alkyl or ar lsidfbnic adds which are imsubstituted or substituted, for example by halogen, for example methyl- or p-toluene- sulfonic acid. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds of the present invention having at least one acid group (for example COOH) can also form salts with bases. Suitable salts with bases are, for example, metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammoni or an organic amine, such s morpholine, thio opaholine, piperidine, pyrrolidine, a mono, di or tri-lower alkylamine, for example ethyl _* terfeb tyl, diethyl, dllsopropyl, Methyl, iributyl or dimethyl-propylamine, or a mono, di or trihydroxy lower allylamiae, for example mono, di or triethanolamine. Corresponding internal salts may furthermore be formed. Salts which are unsuitable for pharmaceutical uses but which can be employed, for exam le, for the isolation or purification of free compounds of Formula (la) or (¾) or their pharmaceutically acceptable salts, are also included.

Preferred salts of the compounds of Formula (la) or (lb) which eoutain a basic group include monohydrochloride, hydrogensulfaie, mcihancsulibnate, phosphate, nitrate or acetate.

Preferred salts of the compounds of Formula (la) or (fb) which contain an acid grou include sodium, potassium and magnesium sails and pharmaceuticall acceptable organic amines.

In addition, compounds of Formula (la) or (lb) may have prodrug forms. Any compound that will be converted in vivo to provide the bioactive agent (he. , a compound of formula la or lb) is a prodrug within tire scope and spirit of the invention. Various forms of prodrugs are well known in the ate. For examples of such prodrug derivatives, see:

a) Bundgaatd, FL ecL Design of Predr ugs, Elsevier (1985k and iddcr, fe. et al, eds,, h-feikods in E ymologv _^ 1 12:509 -396, Academic Press (1985 K

b) Bundgaani H. Chapter 5. "Design and Application of P o mgs", A Textbook of Drug Design a Development, pp 1 13-191 , Krixsgaard-Larsen, Ft et al., eds., Harwood Academic Publishers (1991);

c) Btffidgaard, H , Adv. Drug Del he P e , 8: 1 -3 ( ! 992) ;

d) Bnudgaard, B. ei al, ,1 Pharm Set , 77 285 (1988); and

e) Kakeya, N et a!., Chew. Pharm. Bull , 32:692 (1984).

The compo unds of the present invention contain a carboxy poop which can form physiologically hydrolyzable esters that serve as prodtugs, ie,,“prodrag esters”, by being hydrolyzed in the body to yield the compounds of tire present invention er so. Examples of physiologically hydrolyzable esters of compounds of the present invention include C _j to 9 6 alkyl, C] to Gp alkylbenzyi, 4- ethoxybenz l, indanyl, phtha!yl, ethoxymcfhyl, methyl, plvaioy!oxytnethyl or

propiooyioxy edhyl), C to C¾ alkoxycahony loxy-C _j to Cg alkyl (e.g.,

meihoxycarbonyhoxymethyi or efhoxycarbonyioxymethyl glycyioxymsthyl, phenylgiycyloxyniethyl, (S~meihyl-2-oxoB,3~dioxoIen-4- lVmethyl}, and other well known physiologically hydrolyzable esters used, for ex mple, in. the penicillin and cephalosporin arts. Such esters may be prepared by conventional techniques: known In the art. The ro g esterffi can be formed by reacting the carboxylic acid motet? of the compounds of the present invention with either alkyl or aryl alcohol halide, or sulfonate employing: procedures known to those skilled in the art. Such esters may be: prepared by conventional ieeh iqnes known i the art.

Preparation of prodrugs is well known In the art and described in, for example. King, F.D., ed., Medicinal Chemistry: Princi les and Practic , The Royal Society of Chemistry, Cambridge, UK (1994); Testa, B. ct ai„ Hydrolysis in Drug and Prodrug Metabolism, Chemistry, Biochemistry and Enzymalogy _? VCHA and Wiley-VCIT, Zurich, Switzerland (2003); Wetmuth, C.G., ed . The Practice of Medicinal Chemistry, Academic Press, San Diego, CA ( 1 99).

The present invention is intended to include all isotopes of atoms occurring in the present compounds:. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and withou limitation, isotopes of hydrogen Include deuterium and tritium. Deuterium has one proton and one neutron in its nucleus an that has twice the mass of ordinary hydrogen. Deuterium can be represented by symbols such as " IT" or "D". 1 ^' he term "deuterated" herein, by itself or used to modify a compound or group, refers to replacement of one or more hydrogen atom(s), which is attached to carbon(s ), with a deuterium atom. Isotopes of carbon include C and - ⁱ⁴ C.

Isotopkallydabeled compounds of the invention can generall y be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically- labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds have a variety of potential uses, eg. , as standards and reagents In determining the ability of a potential

pharmaceutical compound to bind to target proteins or receptors, or for imaging compounds of this invention bound to biological receptors in vivo or in vitro,

"Stable compound” and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purit from, a reaction mixture, and formulation into an efficacious therapeutic agent. It is preferred that compounds of the present invention do not contain a -halo, S(0)aB, or S(0)H group. The term foolvats eans a physical association of a compound of this invention ii one or more solvent moleenles. whether organic or inorganic, This physical

association includes hydrogen bonding. In certain instances the solvate will be capable rtf Isolation, tor example, when one or more solvent molecules are incorporated in the crystal lattice of the crystalline so lid. The solvent molecules hi the solvate- ma be present in a regular arrangement and/or a non-ordered arrangement- The solvate may comprise either a stoichiometric or nonstoichiometrie amount of the solvent molecules. "Solvate" encompasses botlr solution-phgse and iso I able solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropano!ates. Methods of solvati on arc generally known in the art

ABBREVIATIONS

Abbreviations as nsed herein, are defined as follows: "1 x" for once, "2 x" tor twice,”3 x" for thrice,” AT for degrees Celsius, "eq" for equivalent or equivalents, "g" for gram or grams "mg" for milligram or milligrams, "L" for liter or liters, "ml," for milliliter or milliliters,“m[," for microBtcr o microliters, "N" for normal, "M" for molar, "mmol" for millimole Or millimoles, "min" for minute or minutes, ¾" for hoar or hours, "it" for room temperature, "RX" for retention time,“RBF” fo round botto flask, "atm” for atmosphere, "psi" for pounds per square inch, "cone " for concentrate, TkCvT for ring-closing metathesis, "sat" or "sat'd " for saturated,“SFC” for supercritical fluid chromatography "MW" for molecular weight, "mp" for .melting point, foe" for enantiomeric excess, "MS" or "Mass Spec" for mass spectrometry, "BSr for electrospray ionization mass spectroscopy, "OR" for high resolution, "1TR.M.S" for high resoluifon mass spectrometry, "LCMS" for liquid chromatography mass spectrometry, "HFM..C ^‘ for high pressure liquid chromatography, "RP HPLC" for reverse phase BPLC, "TLC" or "do" for thin layer chromatography, "NMR." for nuclear magnetic resonance

spectroscopy, "nOe" fi.tr nuclear Overhanser effect spectroscopy, "¾” for proton, for delta, "s" for singlet, "d" for doublet, "t" for triplet, "q" for quartet, "m" for muliiplei, "hr" for broad, "fife" for hertz, and "a", "p", fofo "By and "ST are stereochemical designations familiar to on·.- skilled in the art.

Me methyl Et ethyl pyl

Bu butyl

i~B isobiriyl

f-Bu Arf-butyl

Ph phenyl

Bn benzyl

Hoc or BQC ferPbutyioxyearbonyl

BocaO di- >T~feutyI bicarbonate

AcOH or HO Ac acetic add

aluminum trichloride

Azobis-isobutyronit k

BB boron tribromide

BCb boron trichloride

BEMP 2~kri-bniybrnlno~2 dieihylaminO” 13; dimetbylperhydro- 13,2-- diazaphospborine

benzotdazoi- i-yloxytria(dimethyia o)phosph<.miu

hexafiuorophosphate

B¾pm): bis(pmacolaio)diborr;n

Burge s reagent I-methoxy-N-triethyiammoriiosulfonyl-methanimidate CBz carbobenxyloxy

DEM or Cl-ECb dieMoromethaue

CB CN or ACN acetonitrile

CBCb deniero- chloroform

CH<¾ chloroform

ffiCFBA or m-< B L e -cMoroperbenzoic a d

C¾C ¾ cesium carbonate

Cn(OAc} ₂ copper (11) acetate

CyrN e N-eycIobexyEN-mcthyieyclobeyanamine

DBU 1 Jyliazabicyclo[5 4 0jitrid _: ec--7~e.ue

DCE 1 ,2 dichiomethane DEA Diethyla e

DEAD Diethyl azodi arboxy!&te

Dess-Mardn ! ,1 J -t?is(aeeiyloxy)-l J -dlhydro- 1 A¾en iodoxoh3-( l.iTKme

DIAD Dtisopropyi azodiearhoxylate

DIC or DIPCDI dhsopropylearbodii lde

DO:· A, IMPEAor dlisopropy!ethyiamine

Himig's base

DMA? d-di elhylar nopyridirse

:DME 1 ^- i ethoxyethaae

DMF dimethyl tbrmamids

DMSD dimethyl sulfoxide

eDNA complementary DNA

Dppp (i?}-( }~E2~his(d.ipfen _: ylph©sphino _ji propane

uPhos ( ^; -)~L2~bls((2S,5S)--2 _i 5dietlrylphospholaBo)betmeno

EDO :¥-(3-dimthyIs mopropyl}-A ^' -ctliyicarhodiimide

JV-C3-:di.mthyiara.mopropyi)-A ^r ~etbylcarbodiitnide hydrochloride

EDTA eChyienedkmketetraacetic acid

(S,5)-EtDuPho«Rh(I) ( )~ 1 ,2~hi s((2S _s 5 S}~2 , 5 ~di ethy !phospho 1 ano)benzcne( 1 , $ - ey oociadiene)rhodium(l) tnfiuo methaftesolfoaate

BEN or TEA. inehylan ie

EtOAe ethyl acetate

EbO ietii 1 ether

EOii ethanol

GMF glass microfiber filter

Grubbs P (I21d7is(242->mi edydpherpd}-Aimidazoiid:mylklcne)dic.hk >

(ph.en.ylmetbylene-}(iriycydobexiphosphine)mtbeaiu

HQ hydrochloric acid

HATli 0~{7~azahenzo†naxo 1 - 1 -y 1)-N _; N ,N \N -ietramethyl uronium hexafi uorop hosphate

BEPBS 4~(2-bydroxyetbyl}piperaxine~l~ethais.esidibnie acid

hexane

HOBt or HOBT 1 -hy droxybetmo tr I aole H2O2 hydrogen peroxide

1BX 24o oxyben¾>ic acid

IfiSCfi sulfuric acid

Jones reagent Cri¾ n aqueous II2SO , 2 M solution

¾CC¾ potassium carbonate

Kfi!Kri potassium phosphate dibasic ; potassium hydrogen phosphate)

KOAc potassium acetate

KsfiC-U potassium phosphate tribasie

I. LH lithium aluminum hydride:

LG leaving grou

LiQH lidrium hydroxide

MeOH methanol

MgSCri magnesium sulfate

MsOO or MSA methyisulihnie actd/merhanesulibnic acid

NaCI sodium chloride

mi sodi m hydride

NaHCOj sodium bicarbonate

NaaCOs sodium carbonate

NaOH sodium hydroxide

N¾SO · sodium sulfite

NavSCfi sodium sulfide

NRS N~ htomosueem Iniide

NCS -chlotosucemimide

Nils ammonia

H4CI ammonium chloride

MH4OH ammonium iiy art > x 1 de

Ni fid ICO; ammoni um formate

KMM N-methy!morphot e

on trifiate or trifi wromethanesdfbnaie

Pdaidbap tTis(dibenayl:idexteacetone)dipa!ladlum(0)

Pd(OAc): palladium(ll) acetate

Pd/C palladium on carbon Pd(dppf)€¾ [l ₅ r ~bis(dipbeByIphospMao)-fe;rrocene]dIch!oropaIla4iu (II)

PhjPCfe hiphenylpliospMne dich!oride

PG proieciing group

(PhOhPONs dipheny!pltospharyl azide

POCb phosphorus oxychloride

PF3TS py ridi ni tun p-to 1 ttenesis I fonate

i-PrOH or IP A isopropaodl

PS Polystyrene

RT or it room temperature

SBM-C! ¾^tnmetibysily|)etboxyrn.eihyl chloride

Si O2 silica oxide

Sn€% ίί 0(11) chloride

TBAF fra-»- butyism oni am fluoride

ΎBAΪ ieira-u-butyfamffioniam iodide

TPA triilooroacetk acid

i s IG tebahydrofutan

THP ietrahydrop ran

T SCH a Inmethy!silyldiazomeihane

TMSCHaMi Trimerit lstfylmethyl azide

T3P propane phosphonic acid anhydride

T .iS iris (hydroxymethyl ) aminomethane

p 1 A d i puomencsulibn ic acid

IV. BIOLOGY

Lysophosphobpids are membrane-derived bioaciive lipid mediators.

LysophosphoHpids include:, but are not. limited to, lyxophosphatidic acid (I ~acyt-2- hydro.xy-xu--gIyeero~3-pbospiiatc; LPA), sphmgosine i -phosphate (SIP),

iysophosphatklylcholine (LPC), and spMngosylphospbory [choline (SPG),

Lysophospho!ipids affect fundamental cellular .functions that include cellular

proliferation, differentiation, survival, migration, adhesion, invasion, and morphogenesis. These functions influence: many biological processes that include neurogenesis, angiogenesis, wound healing, immunity, and carcinogenesi . LPA acts through sets of specific G pi olein-coupled receptors (GPCRs) in an autocrine and paracrine fashion. LFA binding to its cognate GPCRs (LPAi, LPA2, LFA3, LPA*, LPAS, LPA$) activates ktraceliulaf signaling pathways to produce a variety of biological responses.

$ Lysophospholipids, such as LPA, are quantitatively minor lipid species compared to their major phospholipid counterparts , phosphatidylcholine,

phospharidylethanolannne, and sphingomyelin). LPA has a role as a biological effector molecule, and has diverse range of physiological actions such as, but not limited to. effects on bloods pressure, platelet activation, and smooth muscle contraction, and a0 variety of cellular effects, which include ceil growth, cell rounding, neurite retraction, and actin stress fiber formation and cell migration. The effects of LPA are predominantly r ocpmr mediated.

Activation of the LPA receptors (LPAs, LPAa, LPAs, LPAa, LPAs, LPAs) with LPA mediates a range of downstream signaling cascades These include, but are not5 limited to, ouiogen-activated protein kinase (MAPK) activation, adenylyi cyclase (AC) Inhibition/activation, phospholipase C (FLC) aerivaiioo/Ca ² mobilisation, araehidonic acid release, Akt/PKB activation, and the activation of small GTPases, Rho, ROCK, RaC, an Ras. Other pathways that are affected by LPA receptor activation include, but are not limited to, cyclic adenosine monophosphate (cAMP), cell division cycle 42/GTP- binding0 protein (Cdc42) , proto-oncogene serinedhteomne-protein kinase Raf (e-RAP), proto- oncogene tyrosine-protein kinase Sre (e~srck extracellular signal-regulated kinase (ERK), focal adhesion kinase (FAR), guanine nucleotide exchange factor (G.BF) glycogen synthase kinase 3b (GSKAb), c-jim amino-terminal kinase (INK), MEK _» myosin light chain II ( LC II), nuclear factor kB (NF~kB), N~raethy !-B-aspartate (NMDA) receptorS activation, phosphatidyi ositol 3-kinase (P13R) protein kinase A (PKA), protein kinase € (PRC), ras-relaled C3 botuHnum toxin substrate 1 (RAC I) The actual pathway and realized end point are dependent on a range of variables that include receptor usage, cell type, expression level of a receptor or signaling protein, and LPA concentration. Nearly all mammalian cells, tissues and organs co-express several LP -receptor subtypes, which0 indicates that LPA receptor signal in a cooperative manner. LPAi, LPAs, and LPA·* share high amino acid sequence similarity. LPA Is produced item activated platelets, activated adipocytes neuronal cells, an other cell types. Serum LPA is produce by multiple enzymatic pa&ways that involve mmioacyl glycerol kinase, phospholipase A}, secretory phospholipase As, ami

!ysophosphallpase D (lysoPLD), including anfotaxm. Several enzymes are involve in $ LPA degradation: lysopliospliolipase, lipid phosphate phosphatase, and LPA. acyl

transferase such as endophilim LPA concentrations in human se um are estimated to he 1-5 mM. Serum LPA is bound to albumin, low-density lipoproteins, or other proteins, which possibly p otect LPA from rapid degradation. LPA molecular species with different acyl chain lengths and saturation axe naturally; occurring. Including l-palmitoyl0 (16:0), l~palnxitofeoyi (16:1), i-stearoyi (1¾:0), 1-oleoyl (18:1), l-lino!eoyl (18:2), and I araehidooyl {20:4} LPA Quantitatively minor alkyl LPA has biological activities similar to acyl LPA, and different LPA species activate LPA receptor subtypes with varied efficacies, 5 Lf A RECEPTORS

LPA r (previously called VZG-· l/BDG-2/mrecl .3) couples with three types of G proteins. Gi _¾ . G _¾ , and Giamp Through activation of these G proteins, LPA induces a range of cellular responses through LPA _? including but not limited to: cell proliferation, serum- response element (SRE) activation, mitogen-activated protein kinase (MAPK) activation,0 adenylyi cyclase: (AC) inhibition, phospholipase C (FLC) activation, Cm ^f mobilization, Akt activation, and RIio activation.

Wide expression of LPA _? is observed in adult mice, with clear presence in testis, brain, heart, lung, small intestine, stomach, spleen, thymus, an skeletal muscle.

Similarly, human tissues also express LPAg it is present in brain, heart, lung, placenta,5 colon, small intestine, prostate, testis, ovary, pancreas, spleen, kidney, skeletal muscle, and thymus.

LPA· (EDG-4) also couples with three types of proteins, G; _/ «, G and Gw¾, to mediate LPA-indueed cellular signaling. Expression of LPA; Is observed in the testis, kidney, lung, thymus, spleen, and stomach of adult mice an in the human testi s,0 pancreas, prostate, thymus, spleen, and peripheral blood leukocytes. Expression of LPA.; is upregu!ated in various cancer cell lines, and several human LPAe transcriptional variants with mutations in the 3 Untranslated region have been observed. Targeted dele ion of LPAc hi mice has not shown: any obvious phenotypic abnormalities* but has demonstrated a: significant loss of normal LPA signaling (e. jp, PLC activation, Ca^ mobilisation, and stress fiber formation) in. primary cultures of mouse embryonic fibroblasts ( EFa) Creation of l/ sd ( /-) !pal (~/~) double-null mice has revealed that many LPArinduced responses, w oh include cell proliferation, AC inhibition, PLC activation, Cr ^:i mobilization, iMK and Akt activation, and stress fiber formation, are absent or severely reduced in double-null EBs, All these responses, except for A.C inhibition (AC inhibition is nearly abolished in LFAi (-/-) MEFs), are only partially affected in either LFAi (-A) or LPAs (Ά) MEFs. LPAe contributes to norma! LPA- mediated signaling responses in at least some cell types (Choi et al Bmchemiea et

Biophysics A&ia 2008, 1781 , p531 -539).

LP s (EDG-7) Is distinct front LFAi and LFAr iu its ability to couple with G _½> and Gy bnt not Gsaas and is much less responsive to LPA species with saturated acyl chains, LPAs can mediate ptelotrople LPArinduced signaling that includes PLC activation, Ca ^2* mobii dtion, AG mfobitiou/aetivafion, and MAP activation.

OveTexpression. of LPAs in neuroblastoma cells leads to neurite elongation, wherea that of LPAs or PA2 results in neurite retraction and ceil rounding whe stimulated with LPA Expression of LPAs Is observed in adult mouse testis kidney, lung, small i ntest loe, heart, thymus, and brain. In humans, it is found in the heart, pancreas, prostate, testis. lung, ovary, and brain (frontal cortex, hippocampus, and amygdala).

LPA.· {p2yyGPR23l is of divergent sequence compared to LPAg LPA _¾ and LPAs with closer similarity to the platelet-activating factor (PAF) receptor, I..PA4 mediates LPA induced Ca^ mobilisation an cAMP accumulation, and functional coupling to the G protein Gs for AC activation, as well as couplin to other G proteins. The LPA gone is expressed in he ovary, ancreas, thymus, kidney and skeletal muscle.

LPAs (GPR92) is a member of the purinoeiuster of GPCRs and is structurally most closely related to LPA*. LPAs is expressed in human heart, placenta, spleen, brain, lung and gut LPAs also shows very high expression in the CDS-*- lymphocyte

compartmen t of the gastrointestinal tract

LPAs p2y5) is a member of the purinoeiuster of GPCRs and is structurally most closely related to LEA,*. LPAs Is an LPA receptor coupled to the G!2/!3~Rho signaling pathways and is expressed in the inner root sheaths of human hair .follicles. Illustrative Biological Activity

Wound Healing

Normal wound healing occurs by a highly coordinated sequence of events ip 5 which cellular, soluble factors and atri components act In concert to repair the injury, The healing response can be described as taking place in four broad, overlapping phases . hemostasis, inflammation, proliferation, and remodeling. Many growth factors and cytokine are released into a wound site to initiate and perpetuate wound healing processes

:0 When wounded, damaged bloo vessels activate platelets. The activated platelets pla pi votal role in subsequent repair processes by releasing bioactive mediators to induce cell proliferation, cell migration blood coagulation, and angiogenesis. UP A is one such mediator that I released from activated platelets; this induces platelet aggregation along with mitogenic/migration effects on the surrounding cells, such as endothelial cells, 5 smooth muscle cells, fibroblasts, and kerat ocytex.

Topical application of LB A to cutaneous wounds in mice promotes repair processes (wound closure and increased oeoepifhehal thickness) by increasing cell proliferation/ migration without affecting secondary inflammation.

Activation of dermal fibroblasts by growth factors and cytokines leads to their0 subsequent migration from the edges of the wound into the provisional matrix formed by the fibrin dot whereupon the fibroblasts proliferate and start to restore the dermi b secreting and organizing the characteristic dermal extracellular .matrix (ECM) The increasing number of fibroblasts within the woun and continuous precipitation ofECM enhances matrix rigidity by applying small traetiona! forces to the newly formed

5 granulation tissue. The increase ia mechanical stress, in con; unction with transforming growth factor P (TGF ) induces «-smooth muscle actin (a-SMA) expression an the subsequent transformation of fibroblasts into myofibroblasts. Myofibroblasts facilitate granulation tissue remodeling via myofibroblast contraction and through the production ofECM components.

0 EM. regulates many important functions of fibroblasts in wound healing.

including proliferation, migration, differentiation and contraction. Fibroblast proliferation is requited i wound healing in order to fill an open wound. In contrast, fibrosis is characterized by intense proliferation and accumulation of myofibroblasts that activel synthesize EGM and proinfla matory cytokines. LPA can either increase or suppress the proliferation of cell types important in wound healing, such, as epithelial and endothelial cells (EC), acrophages, keratinocytes and fibroblasts A role for LPA] in LPA-indueed proliferation was provided by the observation that LPA-stimukted proliferation of fibroblasts isolated from LPAi receptor null mice was attenuated (Mills e:i al, Nm Rev, Cancer 2003; 3: 582-591 ). LTA induces eyfoskeletal changes that are integral to fibroblast adhesion, migration, differentiation /and contraction.

Fibrosis

Tissue nju y initiates a complex series of host wound-healing responses; if successful _* these responses restore normal tissue structure and function. if not. these responses can lead to tissue fibrosis and loss of function.

For fee majority of organs and tissues the development of fibrosis in volves a multitude of events and fectors, Molecules involved In the development of fibrosis Include proteins or peptides (profibrotic cytokines. ©he okine?, meialioprote asea etc ) and phospholipids Phospholipids involved in the development of fibrosis include platelet activating factor (PAP), phosphatidyl choline, sphingosine-I phosphate (SIP) and lysophosphaiidie acid (LPA).

A number of muscular dystrophies are characterized by a progressive weakness and wasting of musculature, an by extensive fibrosis. It has been shown dm LPA treatment of cultured my oblasts induced significant expression of connective tissue growth factor (CTGP). CTGP subsequently induces collagen, fifcroneeiin and integria expression and induces dedifferentiation of these myoblasts. Treatment of a variety of cell types with LPA induces reproducible and high level induction of CTGP (J.P. Pradere, ei at LPAi receptor activation promotes renal Interstitial fibrosis, J. Am; Soc Nephrol. 18 (200?) 31 10-31 I S; N, Wiedmaier, ei aL Ini J Mai Mic hiot 298(3-4);23 i~43, 2008) CTGP is a profibrotic cytokine , signaling down-stream and in parallel ith TGFp.

CTGF expression by gingival epithelial cells, which are involved in the development of gingival fibrom tosis, was found to be exacerbated by LPA treatment (A. ISaoiarci, */ ol J P&fhol 210 (2006) S9-66). LFA is associated. with the progression of liver fibrosis, In vitra, LPA induces Stellate cell and hfepatbcyte proliferation. These activated ceils are the main cell type responsible for the accumulation of ECM in the liver Furthermore, L FA plasma levels rise during CGU-induced liver fibrosis in rodents, or in hepatitis€ virus-induced liver fibrosis in humans (N, Waianabe, or &L _> Plasma !ysopbosphatldlc acid level and serum autotaxisi activity are increased in liver injury In rats in relation to its severity, life ScL SI (200?) 1.009—1015; N Waianabe, ei al, , J Clin. Gastroenterol 41 (2007) 6I6-623)

An increase of phospholipid concentrations in the bronehoalveolar lavage fluid in rabbits and rodents injected with bleomycin has been reported {K. Katroda, ei al., Phospholipid concentration in lung lavage finld as hiornarker for pulmonary fibrosis, Inkal Toxical . 18 (200b) 389~393; K. Yasnda, ei ai , Img I 72 (! 994) 91-102).

LPA is associated with heart: disease, and mycoeardial remodeling Serum LPA levels are increased alter myocardial infarction in patients and LPA stimulates rat cardiac fibtdblast proliferation and collagen production (Cken el ai. FEBSle& 2006 Aug

2l ;580<19);4?37~45).

Pulmonary Fibrosis

In the lung, aberrant wound healing responses to injury contribute to the pathogenesis offibrolic lung diseases Pibrotlc lung diseases, such a idiopathic pulmonary fibrosis (IPP), are associated with high morbidity and mortality,

LPA is an. important mediator of fibroblast recruitment in pulmonary fibrosis.

LPA and LPA* play key pathogenic roles in pulmonary fibrosis. Fibroblast

chemoattractant activity plays an important role In the lungs in patients with pulmonar fibrosis, Profibrohe effects of LP Aj -receptor stimulation is explained b LPA * -receptor mediated vascular leakage and increased fibroblast recruitment, both p ofi brotic events. The LPA-LPAi pathway ha a role in. mediating fibroblast migration and vascular leakage in IPP. The end .result is the aberrant healing process that characterizes this fihrotic condition.

The LPAs receptor is the LPA receptor most highly expressed on. fibroblasts obtained from patients with IFF Furthermore, BAL obtained from IFF patient induced cheniotaxis of human foetal lung fibroblasts that was blocked by the dual LPAi- LPAs receptor antagonist Ki 16425. In an experimental bleomycin-induced lung injury mouse model, it was shown that I .PA levels were high in brondioalveolar lavage sample compared with unexposed controls, LPAr knockout mice are protected from fibrosis after blcontycin challenge with reduced fibroblast accumulation and vascular leakage. In human subjects with IFF high Li A levels were observed in bronchoalveolar lavage samples compared with healt y controls. Increased fibroblast chemoiaciic activity In these samples was inhibited by the Ki 16425 indicating that fibroblast migration is mediated by the LPA-LPA receptoris} pathway (Tager et aL Nature Medkim, 2008» I.4 _> 45-54).

The LPA-LPA; pathway is crucial in fibroblast recruitment and vascular leakage in pulmonary fibrosis

Activation of latent TGF~|¾ by the anb6 integrln plays a critical role in the development of lung injury and fibrosis (Monger er a!. Cel vol 96, 319-328, 1 99), LPA induces vpb-medialed TGF-b activation on human lung epithelial cells ( _* ¾ eial. Am. J Pathology 174, 1264-1279), The LPA-induced avjffi-mediated TGF-b activation is mediated by the LPAe receptor. Expression of tire LP,½ receptor Is increased in epithelial cells and mesenchymal cells in areas of lung fibrosi from IFF patients compared to normal hnm¾n long tissue ThelLPA-LPAs pathway contributes to the activation of the TGF-b pathway in pulmonary fibrosis. In some embodiments, compounds that inhibit LPA·. _? show efficacy in the treatment of lung fibrosis. In some embodiments, compounds that inhibit both LPA; and LPAa sho improved efficacy in the treatment of h g fibrosi compared to compounds which inhibit only LPA; or LPAz.

The LPAi antagonist BMS-986020 was shown to significantly reduce the rate of FVC (force vital capacity) decline in a 26-week clinical trial in IFF patients (Palmer ei ah, Chest, 21118, 154, 106M069). Renal Fibrosis

LPA and LPAi are involved m the etiology of kidney fibrosis. LPA has effects on both proliferation and contraction of glomerular mesangial cells mid thus has been implicated in proliferative glomerulonephritis (C.N, inoue, et at, CHn. Sci. (Colch.) 1999, 96 _f 431 -436), In an animal model of renal fibrosis [unilateral ureteral obstruction (IJUO)), it was found that renal LPA receptors are expressed under basal conditions with an expression order of LPA2>hPAy ^:: LPAi>>LPA4. This model mimics in an accelerated manner the development of renal fibrosis including renal inflammation, fibroblast activation and accumulation of extracellular matrix in the tu ¾loint.efstili]u . UO0 significantly mdnced LPAj-feeeptOr expression; This was paralleled by renal LPA production (3 3 fold increase} in conditioned media from kidney exp!ants. Coutra-latdral kidneys exhibited no significant changes in LPA release and LPA-reeeptom expression, Th s shows that a prerequisite for an action of LPA in fibrosis is met; production: of ligand (LPA) and induction of one of its receptors (the LPA? receptor) (J.P. Pradere AAfi Blochmica et Biaphy ica Acta, 2IMI , iMl, 582-5 $7).

In mice where the LPAj receptor was knocked oat (LPAi (-/-), the development of renal fibrosis as signilicantiy attenuated. tJ0O mice traded with the LPA receptor anlagomv ki 16425 closely resembled the profile ofLPAi ( 7-) ntioe.

LPA cm participate in intraperitoniaS aceurnuiation oilmonocyterinacrophage arid LPA can induce expression of the profibrotic cytokine CTC3F in primar cultures of human fibroblasts (IS Koh,A al, J dm, ImesL, 1998, 102, 716-727),

LPA treatment of a mouse epithelial renal cell lino, MCT, induced a rapid increase In the expression of the profibrotic cytokine CTGF. GTGF plays a crucial role in IJUO- iuduced tubulointerstitial fibrosis (TIP), and is involved in the profibrotic activity of TGPjl This induction was almost completely suppressed by co-treatment with the LPA- receptor antagonist Kil 6425. in one aspect, the profibrotic activity of LPA in kidney results front a direct action of LPA. on kidne cells involving induction of CTGF.

Hepatic fibrosis

LPA is implicated in liver disease and fibrosis. Plasma LPA levels and scru aniotaxm (enzyme responsible for LPA production) are elevated in hepatitis patients and animal models of fiver injury in correlation with increased fibrosis. LPA also regulates liver cell function. LPAj and LPAs receptors arc expressed by mouse hepatic stellate cells and LPA stimulates migration of hepatic myofibroblasts.

Ocular f ibrosis

LPA is in involved in wound healing In the eye. LPAt and LPAs receptors axe detectable in the normal rabbit corneal epithelial cells, keraioeytes and endothelial cells and LPA· and LPA* expression are increased in corneal epithelial cells following injury. LPA and homologues are present in the aqueous humor and the lacrimal gland fluid of the rabbit eye and these levels ere increased in a rabbit corneal injury model.

LFA induces actin stress liber formation In rabbit corneal endothelial and epithelial cells and promotes contraction comes! fibroblasts. LFA also stimulates proliferation of human retinal pigmented epithelial cells

Cardiac fibrosis

LPA Is implicated in myocardial infarction and cardi c fibrosis. Seram LFA levels are increased in patients following mycoeardial infarction (MI) and LPA stimulates proliferation and collage» production (fibrosis) by rat cardiac fibroblasts. Both UFA! and LPA3 receptors ate highly expressed m human heart tissue.

Treatment of Fibrosis

In one aspect, a compoun of Formula (la) or (fbf or a pharmaceutically acceptable salt or solvate thereof is used to treat or prevent fibrosis in a mammal. In one aspect, a compound of Formula (In) or (lb), or a pharmaceutically acceptable salt or solvate thereof is used to treat fibrosis of an organ or tissue in a mammal . In one aspect is a method for preventing a fibrosis condition in a mammal, the method comprising administering to the mamma! at risk of developing one or more fibrosis conditions a. therapeutically effective amount of a compound of Formula (la) or (lb), or a

pharmaceutically acceptable salt or sol vate thereof in one aspect the mammal has been exposed to one or more environmental conditions that are known to increase the risk of fibrosis of an organ or tissue. In one aspect, the mammal has been exposed to one or more environmental conditions that am known to increase the risk of lung, liver or kidneyfibrosis. In one aspect, the mammal has a genetic predisposifi; m of e\ eloping fibrosis of au organ or tissue. In one aspect, a compound of Formula (la) or (lb), or a

pharmaceutically acceptable salt or solvate thereof, is administered to a mammal to prevent or minimize scarfing following injury. In one aspect, injury includes sweeps

The terms“fibrosis” or "fibrosing disorder,” as used herein, refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include but are not limited to fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.

Exemplary diseases, disorders, or conditions that involve fibrosis Include, but are not limited to: Lung diseases associated with fibrosis, e.« , idiopathic pulmonary fibrosis, pulmonary fibrosis secondary to systemic Inflammatory disease such as rheumatoid arthritis, scleroderma, lupus, cryptogenic fibrosing alveolitis, radiation induced fibrosis, chronic obstructive pulmonary disease (COPDf scleroderma, chronic asthma, silicosis, asbestos induced pulmonary or pleura! fibrosis, acute lung injury and acute respiratory distress (including bacterial pneumonia induced, trauma induced, viral pneumonia induced, ventilator induced, eon-pulmonary sepsis induced, and aspiration induced); Chronic nephropathies associated with injury/Sbro sis (kidney fibrosis), e g ,

glomerulonephritis secondary to systemic inflammatory diseases such as lupus and scleroderma, diabetes, glomerular nephritis, ideal segmental glomerular sclerosis, IgA nephropathy, hypertension, allograft and Alport; Got fibrosis, e.g; , scleroderma, and radiation Induced gut fibrosis; Liver fibrosis, e g. , cirrhosis, alcohol induced liver fibrosis, nonalcoholic steatobepafiMs (HASH), bili ry duct injury, primar biliary cirrhosis, infection or viral induced liver fibrosis (e.g , chronic BCV Infection), and autoimmune hepatitis; Head arid neck fibrosis, eg., radiation induced; Corneal scarring, e.g., LAS IK (laser-assisted in situ keratomileusis), corneal transplant, and trabeculectomy;

Hypertrophic scarring and keloids, e.g , burn induced or surgical; and other fibro!k diseases, e.g: , sarcoidosis, scleroderma, spinal cor injinry/fibrosis, myelofibrosis, vascuiar restenosis, atherosclerosis, arteriosclerosis, Wegener's granulomatosis, mixed connective tissue disease, and Peyronie's disease.

In one aspect, a mammal suffering from one of the following non-limiting exemplary diseases, disorders, or conditions will benefit from therapy with a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or sol vate thereof:

atherosclerosis, thrombosis, heart disease, vasculitis, formation of scar tissue, restenosis, phlebitis, COPD (chronic obstructive pulmonary disease), pulmonary hypertension, pulmonary fibrosis, pulmonary inflammation, bowel adhesions, bladder fibrosis and cystitis, fibrosi of the nasal passages sinusitis, inflammation mediated by neutrophils, and fibrosis mediated by fibroblasts. in one aspect, a compound of Formula or (lb), or a pharmaceutically acceptable salt or solvate thereof, Is administered to a mamma! with fibrosis of an organ or tissue or with a. predisposition of developing fibrosis of an organ or tissue with one or more other agents that are used to treat fibrosis. In one aspect, the one or more agents include corticosteroids. In one aspect, the one or more agents Include

immunosuppressants. In one aspect, the one or more agents include B-cell antagonists. In one aspect, the one or more agents Include uteroglobin.

In one aspect, a compound of Formula (la) or (lb), or a pharmaceuticall acceptable salt or solvate thereof Is used to treat a dermatological disorders in a mammal. The term ^dermatological disorder,” as used herein refers to a skin disorder. Such dermatological disorders include, but. are not limited to, proliferative or inilanimatory disorders of the skirt such as, atopic dermatitis, bullous disorders, eollagenoses, psoriasis, seieroderma, psoriatic lesions, dermatitis, contact dermatitis, eczema, urticaria, rosacea, wound healing, scarring, hypertrophic scarring, keloids, Kawasaki Disease, rosacea, S _j ogren-Larsso Syndrome, urticaria. In one aspect, a compound of Formula (In) or (lb), or a pharmaceuticall acceptable salt or solvate thereof Is used to treat stwiemle sclerosis.

Pain

Since LPA is released following tissue injury, LPA? plays an i ortant role I» the initiation of neuropathic pain. LPA _? , unlike LPAj or LPAs, is expressed in both dorsal root ganglion (DRG) and dorsal root neurons. Using the antisense oligodeoxynucleotk (AS-ODN) fiat LPAi and LPAi-nuH mice, it was found that LPA -in uced mechanical a!iodyoia and hyperalgesia Is niediated in an LPAi-dependcrrt manner LPAi and downstream Rho-ROCK activation play a role in the initiation of neuropathic pain signaling, Preireatment with Clostridium hoiu!inum C3 exoen yrne (BoTXC3, Rho inhibitor) or Y-27632 (ROCK inhibitor) completely abolished the a!lodynia and

!iyperalgesia in nerve-injured mice. LPA also induce demyeimation of the dorsal roof which was prevented by BoTX< '3. Hie dorsal root demyelination by injury was not observed in LPA _} -«Ml mice or AS-ODN injected wild-type mice. LPA signaling appears to induce important neuropathic pain markers such as protein kinase ϋg (PK.Oy) and a voltage-gated calcium channel «281 subunit (Cao251 ) in an LPAi and Rho- dependent

SO manner (M. Indus ei al , Initiation of neuropathic pain requires lysophosphaiidie acid receptor signaling, Nat Mai 10 (2004) 712-71 S).

In one aspect, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof is used in tbs treatment of pain in a mammal. In one aspect, the pain is acute pain or chronic pain in another aspect, the pain is neuropathic pain

In one aspect, a compound of Formula (la) or(Ih), or a pharmaceutically acceptable salt or solvate thereof is used in the treatment of fibromylagia. In one aspect, fibromyalgia stems from the formation of fibrous scar tissue in contractile (voluntary) muscle-3. Fibrosis binds the tissue and inhibits blood flow, resulting in pain.

Cancer

Lysophospholipid receptor signaling plays a role in the etiology of cancer

Lysophosphafidie acid (LPA) and its G protelmcoupled receptors (GPCIfs) LPAi, LPAj, and/or LPAs play a tele in the development of several types Of cancers. The initiation, progression and metastasis of cancer involve several concurrent and sequential processes Including cell proliferation and growth, survival and anti -apoptosis, migration of celts, penetration of foreign cel ls Into defined cellular layers and/or organs, and promotion of angiogenesis. The control of each of these processes by LPA signaling in physiological aucl pathophysiological conditions underscores the potential therapeutic usefulness of modulating LPA si gnaling pathways for the treatment of cancer, especially at the level of the LPA receptor or ATX/lysoPLD. Aatotaxin ( ATX) is a. prometastatic enzyme initially Isolated from the conditioned medium of human melanoma cells that stimulates a myriad of biological activities, including angiogenesis and the promotion of cell growth, migration, survival, and differentiation through the production of LPA (Mol Cancer liter 200A7i tO j-3552-62)

LPA signals through its o n GPCRa leading to activation of multiple downstream effector pathways. Such downstream effector pathways play a role in cancer LPA and Us OPCRs are linked to cancer through major oncogenic signaling pathways.

LPA contributes to tumorigenesis by increasing motility and iovasiveness of cells, LPA has been implicated in the initiation or progression of ovarian cancer LPA is present at significant concentrations (2-80 mM) in the ascitic fluid of ovarian cancer patients. Ovarian cancer cells eonstfrotively produce increase amounts of LPA as compared to normal ovarian surface epithelial cells, the precursor of ovarian epithelial cancer.

Elevate LPA levels arc also detected In plasma from patients with eariy-stage ovarian cancers compared with controls. LPA receptors (LPAa and PAS) axe also overexpressed in ovarian cancer cells as compared to normal ovarian surface epithelial cells. LPA stimulates Cox~2 expression through t anscriptional acti vation and post-transcriptional enhancement of€ox~2 RN A in ovarian cancer cells. Prostaglandins produced by Cox A have been Implicated in a number of human cancers and pharmacological inhibition of Cox-2 activity reduces colon cancer development and decreases the size and number of adenomas in patients with familial adenomatous polyposis, LPA has also been implicated in tiie initiation or progression: of prostate- cancer, breast cancer, melanoma, head ami neck cancer, bowel cancer (colorectal cancer), thyroid cancer and other cancers (Gardell et aL Trends in Molecular Medicine, voi . 12, no 2, p 65-75, 2006; Ishii et aL Anna Rev B chem , 73, 321-354, 2004; Mills del, Nat. Rev Cancer , 3, 582-591, 2003; Murph et «/,, Bioehimmci et Biophysiea Acta, 1781, 547-557, 2008),

The cellular responses to LPA are mediated through the iysophosphatkile- acid receptors For example, IIP A receptors mediate both migration of and invasion by pancreatic cancer cell lines: an antagonist of LPA} and LPAs (Ki 16425) and LPA _{¾ ~} specific siKNA effectively blocked in vitro migration in response to LPA and peritoneal flui (ascites) from pancreatic cancer patients; In addition Ki 16425 blocked the LPA- induced and ascites-induced Invasion activity of a highly peritoneal metastatic pancreatic cancer cell line (Yamada et al, J Biol Chem 279, 6595-6605 _. , 2004).

Colorectal carcinoma cell lines show significant expression ofLPAt m!INA and respond to LPA by cell migration and production of angiogenic factors. Overexpression of LPA receptors has a role in the pathogenesis of thyroid cancer. LPAs was originally cloned from prostate cancer cells, concordant with the ability of LPA to induce autocrine pro lifer ation of prostate cancer ceils

LPA has stimulatory roles in cancer progression in. many types of cancer LPA is produced from and Ind aces proliferation of prostate cancer cell lines LPA induces human colon careinoom DLDl cell proliferation, migration, adhesion, and secretion of angiogenic factors through LPAi signaling. In other human colon carcinoma ceils lines (HT29 and WiDR), LPA enhances ceil proliferation and secretion of angiogenic factors. fa other colon cancer cell lines, LPA* and LPAa receptor activation results in proliferation of the cells. The genetic or phar acolo ical manipulation of CPA metabolism, specific blockade of receptor signaling and/or inhibition of downstream signal transduction pathways, represent approaches for cancer therapies.

It has been reported that LPA and other phospholipids stimulate expression of inter!euMmS (IL-8) in ovarian cancer cell lines. In some embodiments, high

concentrations of IL-8: in ovarian cancer correlate -with poor initial response to

chemotherapy and with poor prognosis respectively. In animal models expression of IL- 8 and other growth factors such as vascular endothelial growth factor (VEGF) i associated with increased tnmorigeaicify, ascites formation, angiogenesis, and

invasiveness of ovarian cancer cells. In some aspects. IL-8 is an important modulator of cancer progression, drug resistance, and prognosis in ovarian cancer. In some

embodiments, a compound of Formula (la) or (lb) inhibits or reduces 11,-8 expression in ovanan cancer cell lines.

In one aspect, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thcreofi is used in the treatment of cancer. In one aspect, a compound of Formula (la) or Ob), or a pharmaceutically acceptable salt or solvate thereof, is used in the treatment of malignant and benign proliferative disease. In one aspect, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, is used to prevent or reduce proliferation of tumor cells, Invasion and metastasis of carcinomas, pleural mesothelioma (Yamada, Cancer Set, 2008, 99(8), 1603-1610) or peritoneal mesothelioma, cancer pain, bone metastases (Boucbaraba eiai J dirt invest , 2004, 1.14(12), 1.714-1725; B ucharafea ei al _> ro . Nad. acad Sc/., 2006, 103(25) 9643 -9648). In one aspect is a method of treating cancer in a mammal, the method comprising administering to the mammal a eompmmd of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof _» and a second therapeutic agent, wherein the second therapeutic agent is an anti-cancer agent.

The terra "'cancerA as used herein refers to an abnormal growth of cells which tend to proliferate in an uncontrolled way and, in some cases, to metastasize (spread). Th types of cancer include, but is not limited to, solid tumors (such as those of the bladder, bowel, brain, breast, endometrium, heart, kidney, lung, lymphatic tissue (lymphoma.), ovary, pancreas or other endocrine organ (thyroid), prostate, skin (melanoma or basal cell cancer) or hematological tumors (such as the leukemias) at any stage of the disease with or without meiastases.

Additional non-limiting examples of cancers include, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, anal cancer, appendix cancer, astrocytomas atypical teratoid/rhabdaid tumor, basal cell carcinoma, bile duct cancer, bladder cancer, bone cancer (osteosarcoma and malignant fibrous histiocytoma), brain stem glioma, brain tumors, brain and spinal cord tumors, breast cancer, bronchial tumors, Burkit lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T~ Cell lymphoma, embryonal tumors, endometrial cancer, ependymoblastom ,

ependymoma, esophageal cancer, swing sarcoma family of tumors, eye cancer, retinoblastoma, gallbladder cancer, gastric (stomach) cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gastrointestinal stromal cel! tumor, germ cell tu or, glioma, hairy cell leukemia, head and neck cancer, hepatocellular (liver) cancer, Hodgkin lymphoma, hypopharyugea! cancer, intraocular melanoma, islet ceil tumors (endocrine pancreas), Kaposi sarcoma, kidne cancer, Langerhans cell histiocytosis, laryngeal cancer, leukemia. Acute lymphoblastic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, hair cell leukemia, liver cancer, non-small cel! lung cancer, small cell lung cancer, Burkiit lymphoma, cutaneous T-oeil lymphoma, hkrigkin lymphoma, non-Hodgkin lymphoma, lymphoma, Waldenstrom macroglobafine ia, medulloblastoma, medulloephhelioroa, melanoma, mesothelioma, mouth cancer, chronic myelogenous leukemia, myeloid leukemia, multiple myeloma, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, oou-smail cell lung cancer, oral cancer, oropharyngeal cancer, osteosarcoma, malignant fibrous histiocytoma of hone, ovarian cancer, ovarian epithelial cancer, ovarian germ cell tumor, ovarian low malignant potential tumor, pancreatic cancer,

papillomatosis, parathyroid cancer, penile cancer, pharyngeal cancer pineal parenchymal tumors of intermediate differentiation, pineoblasioma and supratentorial primitive neuroectodermal tumors, pituitar tumor, plasma ceil neop!asm/tnultlpk myeloma, pfeurepnlnicmary blastema, primar central nervous syste lymphoma, prostate cancer, rectal cancer, renal cell (kidney) cancer, retinoblastoma, rhabdomyosarcoma, salivar gland cancer, sarcoma, Ewing sarcoma .family of tumors, sarcoma, fcaposi, Se ary syndmme, skin cancer, small ce l Lung cancer, small intestine cancer, soft tisane sarcoma, squamous cell carcinoma, stomach (gastric) cancer, supratentorial primitive

neuroectodermal tumors, T~ce!l lymphoma, testicular cancer, throat: cancer, thymoma and thymic carcinoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenst.rdm acrogiobulmemia, Wilms tumor.

The increased concentrations of LPA and vesicles In ascite fro ovarian cancer patients an breast cancer ei&ssions indicate that it could be an early diagnostic marker, a prognostic indicator or an indicator of response to therapy (Mills et a/, Na Rev. Cancer., 3, 582-591, 2003; Sutphen et al _f. Catie& Epidemiol. Biomarkers Prev. 13, 1 185-1191, 2004). LPA concentrations are consistently higher in ascites samples than In matched plasma samples. espirator a«d Allergic Mwr ers

In one aspect, LPA is a contributor to the _: pathogenesis of respiratory diseases. In one aspect the respiratory di sease is asthma. Irioinfiannnatory effects of LPA include degrauula iion of mast ceils, _: contraction of smooth-muscle cells and release of cytokines from dendritic cells. Airway smooth muscle ceils, epithelial ceils and lung fibroblasts all show responses to LPA. LPA Induces the secretion of IL-8 from human bronchia! epithelial cells. IL~8 is found in increased concentrations in BA I., fluids from patients with asthma, chronic obstructive lung disease, pulmonary sarcoidosis and acute respiratory distress syndrome and 11-8 has been shown to exacerbate airway Inflammation and airway remodeling of asthmatics. LPA], LPAs and LPA* receptors have all been shown to contribute to the LPA-imlueed IL-8 production. Studies cloning multiple GPCRs that are activated by LPA allowed the demonstration of the presence of rnRNA for the LPAi, LPA _¾ and LPAj In the lung ( J. LA. Centos, el ., Mol. Phorm oL 58, 1188-1196, 2000).

The release of ( PA fro platelets activated at a site of injury and its ability to promote fibroblast i o!ifcrati n and contraction are features of LPA as a mediator of wound repair. In the context of airway disease, asthma is an Inflammator disease where inappropriate airway“repair* ^* processes lead to structural“remodeling ^* of the airway, In asthma, the cells of the airway are subject to ongoing injury due to a variety of insults, including allergens, pollutants, other inhaled environmental agents, bacteria and viruses, leading to the chronic aif!annnadon that characterises asthma. 3 In one, aspect, in the asthmatic individual, t e release of norma! repair mediators, including I, PA, is exaggerated or the actions of the repair mediators are Inappropriately prolonged leading to inappropriate airway remodeling. Major structural features of the remodeled airway observed in asthma include a thickened lamina reticularis (the basement membrane-like structure just beneath the airway epithelial cells), increased numbers and _: activatio of yofibroblasts, thidkemng of the smooth muscle layer, increased numbers of mucus glands and mucus secretions, and alterations in the connective tissue and: capillary bed throughout the airway wall. In one aspect, LPA contributes to these structural changes in the airway. In one aspect, LPA is Involved in acute airway hyperresponsiveness in asthma. The lumen of the remodeled asthmatic airway is narrower due to the thickening of the airway wall, thus decreasing airflow. In one aspect, LPA contributes to the long-term tructural remodeling and the acute hyperresponsAeness of the asthmatic airway. In one aspect LPA contributes to the hyper- responsiveness that is a primary feature of acute exacerbations of asthma

in a i ion to the cellular responses mediated by LPA, several of the LPA signaling pathway components leading to these responses are relevant to asthma EOF receptor opregnlatlon is Induced by LPA and is also seen in asthmatic airways (M.

Amishima, er of, A . J Respir Crit Care Med 157, 1907- 1912, 1998), Chronic Inflammation is a contributor to asthma, and several ot the transcription factors that are activated by LPA are known to be I volved in inflammation (Ediger et al _f Ear Respir J 21:759-769, 2003)

in one aspect, the fibroblast proliferation and contraction and extracellular matrix secretion stimulated: by LPA contribute to the fibroprohferstive features of other airway diseases, such as the peribronchiolar fibrosis present in chronic bronchitis _. , emphyw a, and interstitial lung disease, Emphysema Is also associated with a. mild fibrosis of the alveolar wall, a feature which Is believed to represent an attempt to repair alveolar damage. In another aspect, LPA plays a role in the fibrotic Interstitial lung diseases and obliterative bronchiolitis, where both collagen and myofibroblasts are increased. In another aspect, LPA is involved in several of the various syndromes that constitute chronic obstructive pulmonary disease.

Administration of LPA in vivo .induces airway hyper-responsiveness, itch-scratch responses, infiltration and activation of eosinophils and neutrophils, vascular remodeling. and nociceptive flexor responses LPA also indnces: histamine release from moose and rat mast cells. la an acute allergic reaction, hisrimine induces various responses, such as eoniraoiioa of smooth muscle, plasma exudation, and mucus production. Plasma exudation is important in the airway because the leakage and subsequent alrway-waii edema contribute to the development of airway hyper-responsiveness Plasma exudation progresses to eonjuaetival swelling in ocular allergic disorder aid nasal blockage in allergic rhinitis (Hashlmoio er nf, J Pk rmmoi Sd 100, 82 - 87, 2006). hi one aspect, plasma exudation induced by FPA is mediated by histamine release from mast cells vi one or more LPA receptors. la one aspect, the LPA recepior(s) include LPA* and/or LPA*. In one aspect a compound of Formula (la) or (lb), o a pharmaceutically acceptable salt or solvate thereof is used in the treatment of various allergic disorders in a mammal In one aspect n compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof is used in the treatment of respiratory diseases, disorders or conditions in a manmiaL In one aspect, a compound of Formula (la) or (lh), or a pharmaceuticall acceptable salt o solvate thereof is used in the treatment of asthma in a. mammal in one aspect, a compound of Formula i la) or (lb), or a pharmaceuticallyacceptable salt or solvate thereo is used in the treatment of chronic asthma in a mammal.

The term "respiratory disease,” as used lierein, refers to diseases affecting the organs that me involved in breathing, such as the nose, throat, larynx, custo y a» tubes, trachea, bronchi, lungs, related muscles (e.g. , diaphram and intercostals), and serves. Respiratory diseases include, but are not limited to, asthma, adult respiratory distress syndrome and allergic (extrinsic) asthma, nan-allergic (intrinsic) asthma, acute severe asthma, chronic asthma, clinical asthma, nocturnal asthma, allergen -induced asthma, aspirin- ensitive asthma, exercise-induced asthma, isocapoic hyperventilation, child-onset asthma, adult-onset asthma, cough-variant asth occupational asthma, steroid-resistant asthma, seasonal asthma, seasonal llergic rhinitis, perennial allergic rhinitis, chronic obstructive pulmonary disease, including chrome bronchitis or emphysema, pulmonary hypertension, Interstitial lung fibrosis and/or airway inflammation and cystic fibrosis, and hypoxia.

The term "asthma” as used herein refers to any disorder of the lungs characterised by variations in pulmonary gas flow associated with airway constriction of whatever cause (intrinsic, extrinsic, or both; allergic or non-allergic), The term asthma ma he used with one or more adjectives to indicate cause,

kron aspect presented herein is the use of a. compound of Formula (la) or Ob), or a pharmaceutically acceptable salt or solvate thereof) In the treatment or prevention of: chrome obstructive pulmonary disease in a mamma! comprising administering to die mamma! at least once an effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate t reof. In addition, chronic obstructive pulmonary disease includes, but is not limited to, chronic bronchitis or emphysema, pulmonary hypertension, interstitial lung fibrosis and/or airway

inflamma ion, and cystic fibrosis. ervous System

The nervous system is a major locus for LPA* expression; there it is spatially and temporally regulated: throughout brain development. Oligodendrocytes, the myelinating ceils In the central nervous system (CHS), express LFA in mammals, hi addition,

Schwann cells, the myelinating cells of the peripheral nervous system, also express LFA;, which is involved in regulating Schwann cell survival and morphology. These

observations identify important functions for receptor-mediated LFA signaling in neurogenesis, ceil survival, and myelination.

Exposure of peripheral nervous system cell lines to LFA produces a rapid retraction of their processes resulting in cell rounding, which was, in part., mods imd by polymerization of the actio cy toskeleton. In one aspect, LFA causes neuronal

degeneration under pathological conditions when the blood-brain barrier is damaged and serum components leak Into the brain (Miooleoaar, Caen Opin. Ceil BioL 7:203-10 1995). Immortalized ONE neurobiasi cell lines from the cerebral cortex also display retraction responses to LFA exposure through R!io activation and aetomyO

interactions in one aspect, LFA is associated with post-ischemic neural damage (X Neurockem. 61, 340, 1993; J Neu chem 70:66, 1998)

In one aspect, provided Is a compound of Formula (la) or (Ih), or a

armaceutically acceptable salt or solvate thereof for use in the treatment or prevention of a nervous system disorder in a mammal. The term“nervous system disorder, ⁵ ' as used herein, refers to condi tions that alter the structure or function of the brain, spinal cord or peripheral nervous system, including but not limited to Alzheimer ^' s Disease, cerebral edema, cerebral ischemia, stroke, multiple sclerosis, neuropathies, Parkinson’s Disease, those found after blunt or surgical trauma (including post-surgical cogniti ve dysfunction and spinal cord or brain stem injury), as well as the neurological aspects of disorders such as degenerative disk disease and sciatica.

In one aspect, provided is a compound of Formula (la) or (lb), or a

pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a CMS disorder In a mammal. CMS disorders indude, hut are not limited to, multiple sclerosis, Parkinson's disease, Alzheimer s disease, stroke, cerebral ische ia, retinal Ischemia, post-surgical cognitive dysfunction, migraine, peripheral

neuropethy/neuropaihic pain, spinal cor injury, cerebral edema and head injury.

Cardiovascular Disorders

Cardiovascular phenotypes observed after targeted deletion of !ysophospholipid receptors reveal important roles for lysophosplholipid signaling in the development and maturation of blood vessels, formation of atherosclerotic plaques and maintenance of heart rate (lahii, 1. et at Anrm. Rev Biockem . 73, 321-354, 2004) Angiogenesis, the formation of new capillary networks from pre-existing vasculature, is normally Invoked in wound healing, tissue growth and myocardial angiogenesis after ischemic injury. Peptide growth factors (e.g: vascular endothelial growth factor (VEGF)) and

iysophosphoiipids control coordinated proliferation., migration, adhesion, diftcrentiafinn and assembly of vascular endothelial cells (VBCs) and surrounding vascular smooth- muscle cell (VSMCs). In one aspect, dysregulation of the processes mediating angiogenesis leads to atherosclerosis, hypertension, tumor growth, rheumatoid arthritis and diabetic retinopathy (Osborne, Ml and Stalnier, D. Y. Amu, Rev Physiol, 65. 23-43, 2003).

receptors meiude

Rac -dependent iamellipodk formation (e.g LFAi) and Rho-depend t stress-fiber formation (e.g. LPAi), which is important 1» cell migration and adhesion. Dysfunction of the vascular endothelium can shift the balance from vasodilatation to vasoconstriction and lead to hypertension and vascular remodeling, which are risk factors for atherosclerosis (Maguire, J.J. eta!.. Trends Pharmacol $ti. 2i 448.154. 2005} LPA contributes to both the early phase (barrier dysfunction md monocy e adhesion of the endothelium) and the e phase (platelet activation and intra-arterial thrombus formation) of atherosclerosis, in addition to its overall progression. the early phase, LPA torn numerous sources accumulates in lesions and activates its cognate GPCRs (LFAj and LPAs) expressed on platelets (Siess, W, Biockim Biopkys Acta ISS2, 204-215, 2002; Rothep E. et&l. Circulation 108, 741-747, 2003) This triggers platelet shape change and aggregation, leading to intra-arterial thrombus formation and, potentially, nryocardial infarction and stroke. In support of its atherogenic activity, LPA can also be a mitogen and otogen to VSMGs an an activator of endothelial cells and macrophages. In one aspect, mammals with cardiovascular disease benefit from LPA receptor antagonists that prevent thrombus and neointima plaque form ation

In one aspect, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, is used to treat or prevent cardiovascular disease in mammal,

The term Cardiovascular disease,” as used herein refers to diseases atfoeting the heart or blood vessels or both, includin but not limited to: arrhythmia (atrial or ventricular or: both); atherosclerosis and its sequelae; angina; cardiac rhythm disturbances; myocardial ischemia; myocardial infarction; cardiac or vascular aneurysm; vasculitis, stroke; peripheral obstructive attenopaih of a limb, an organ, or a tissue; reperfusion injury following ischemia of the brain, heart or other organ or tissue; endofoxic, surgical, ot traumatic shock; hypertension, valvular heart disease, heart failure, abnormal blood pressure; shock; vasoconstriction (including that associated with migraines); vascular abnormality. Inflammation, insufficiency limited to a single organ or tissue,.

In one aspect, provided herein are methods for preventing or treating

vasoconstriction, atherosclerosis and its sequelae myocardial ischemia, myocardial infarction, aortic aneurysm, vasculitis and stroke comprising administering at least once to the mammal an effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof or pharmaceutical composition or medicament which Includes a compoun of Formula (la) or (fb), or a pharmaceu tically acceptable salt or: solvate thereof

Ih one aspect provided herein arc methods for reducing cardiac reperfnsion injury following myocardial Ischemia and/or endotoxie shock comprising administering at least once to the mammal an effective atnountof at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

In one aspect, provided herein are methods tor re ucing the constriction of blood vessels In a mammal comprising administering at least once to the ammal an effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt o solvate thereof

In one aspect, provided herein are methods for lowering or preventing an increase in blood pressure of a mammal comprising administering at least once to the mammal an effective amount of at least one compound of For ula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

Inflam ation

Lf A has been shown to regulate i trmnologieal responses by modulating aedvides/fimetions of Immune ceils such as TAR-lymphocytes and macrophages. In activated T ceils, LPA activates IL~2 producilon/eell proliferation through LPA; (Gardell et al, TRENDS in Molecular Medlcim Vol 12 \ ^? e 2 February 2006) Expression of LPA- induced Inflammatory response genes is mediated by LFA; and LFAs ( ocltem Biophys Res Commm. 363(4):1001-8, 2007). In addition, LPA modulates the ehemotaxis of inflammatory cells ijiiochem BiophysRes Commun , 1993, 15:193(2}, 497), The proliferation and cyiokme-secreting activity In response to LPA Ofimmune cells ( J.

Immmoi. 1999, 162, 2049), platelet aggregation activity in response to LPA acceleration of migration acti vity i monocytes, activatio of MF-kB in fibroblast, enhancement of fibiunectin-binding to the cell surface, and the like are known. Thus, LPA is associated with various flaniniatory/it msne diseases.

In one aspect, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof is used to treat or prevent inflammation in a mammal. In one aspect, antagonists of LPA; and/or LPA _? fin use in the treatment or prevention of inflammatory/iruniune disorders in a mammal. In one aspect, the antagonist of LPAj Is a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

Examples of mfiammaiory/irranune disorders Include psoriasis rheumatoid arthritis, vasculitis, inSammaioty bowel disease, dermatitis, osteoarthritis, asthma.

6 inflammatory muscle disease, allergic rhinitis, gim% interstitial cystitis, scleroderma, eczehxa, allogeneic or xenogeneic tratsp!afttation (organ, bom marrow, stem cells and other cells arid tissues) graft rejection graft- versusdmst disease, lupus erythematosus, inftsi maiory disease, type I diabetes, pulmonary fibrosis, dermato yosiis. fijogrerfs syndrome thyroiditis (fig., Hashimobfs and autoimmune thyroiditis), myasthenia gravis, autoimmune hemolytic anemia, multiple sclerosis, cystic fibrosis, chronic relapsing hepatitis, primary biliary cirrhosis, allergic conjunctivitis a d atopic dermatitis

Other Diseases, Disorders or Omni if ions

In accordance with one aspect, are methods for treating, reventing, reversing, halting or slowing the progression of LPA-dependent or LFA- ediatcd diseases or conditions once it becomes clinically evident, or treating the symptoms associated with or related to LPA-dependent or LPA-mediated diseases or conditions, by administering to the mammal a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof. In certain embodiments, the subject already has a LPA-dependent or LFA-mediatcd disease or condition at the time of administration, or is at risk of developing a LPA-dependent or LPA-mediaied disease or condition.

In certain aspects, the activit ofLJLAa in a maaimai is directly or indirectly modulated b the administration of (at least once) a therapeutically effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof Such modulation includes, bulls not limited to, reducing and/or lubihiung the activity of LPAjs In additional aspects, the activity of LPA in a mammal is directly or indirectly modulated, including reducing and/or inhibiting, by the administration of (at least once) a therapeutically effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof. Such modulation includes, hut. is not limited to, reducing and/o inhibiting the amount and/or activity of a LPA receptor. In one aspect, the LPA receptor is LPAo

In one aspect, LPA has a contracting action cm bladder smooth muscle cell isolated from bladder, and promotes growth of prostate-derived epithelial cell (A

Urology, 1999, 162 1779-1784; A Urology, 2QQ0, 163, 1027-1032). In another aspect, LPA contracts the urinary tract and prostate in vitro and increases mtraureihral pressure in vivo (WO 02/062389). In certain aspects, are methods for preventing or treating eosinophil and/or basophil and/or dendritic celt and/or neutrophil and/or monocyte aad or T-c l recruitment comprising administering at least once to the mammal an effective amount of ai least one compound of formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

In certain aspects, are methods for the treatment of cystitis, including, e.g , interstitial cystitis, comprising administering at least once fo the mammal atherapeutically effective· amount of ai least one co oun of Formula (la.) or (lb), or a pharmaceutically acceptable salt or solvate thereof

I accordance with one aspect, methods described heroin Include the diagnosis or determination of whether or not a patient is suffering from a I/RD -dependent or I,FA- mediated disease or condition by administering to the subject a therapeutically effective amount of a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof; and determining whether or net the patient responds to the treatment. in one aspect provided herein are compound of Formula (la) or (lb),

pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and

pharmaceutically acceptable solvates thereof which are antagonists of LPAi, and are used to treat patients suffering from one or more LPA-dependeni or LFA-mediated conditions or diseases, including, but not limited to, lung fibrosis, kidney fibrosis, liver fibrosis, scarring sthm , rhinitis, chronic obstructive pulmonary disease, pulmonary hypertension, interstitial lung fibrosis, arthritis, allergy, psoriasis, inflammatory bowel disease, adult respiratory distress syndrome, myocardial infection* aneurysm, stroke, cancer, pain, proliferative disorders and inflammatory conditions. In some embodiments, LPA-dependent conditions or diseases include those wherein an absolute or relative excess of LPA is present and/or observed.

In any of the aforementioned aspects the LPA-dependent or LFA- ediatcd diseases or conditions include, but are not limited to, organ fibrosis, asthma, allergic disorders, chronic obstructive pulmonar disease, pulmonary hypertension, lung or pleural fibrosis, peritoneal fibrosis, arthritis, allergy, cancer, cardiovascular disease, n t. respiratory distress syndrome, myocardial infarction, aneurysm, stroke, and cancer.

In one aspect, a compound oi formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, is used to improve the corneal sensitivity decrease caused by comeal operations such as laser-assisted in situ keratomileusis (LASIK.) or cataract operation, comeal sensitivity decrease caused by corneal degeneration, and dry eye symptom caused thereby.

in one aspect, presente herein i s the use of a co pound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, in the treatment or prevention of ocular inflammation and allergic conjuncti vitis, vernal keratoconjunctivitis, an papillary conjunctivitis In a mammal comprising administering at least owe iso the mammal an effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

In one aspect, presented herein is the use of a compound of Formula (fa) or (lb), or a phar ceutically acceptable salt or solvate thereof in the treatment or prevention of Sjogren disease or inflammatory disease with dry eyes in a mammal comprising administering at least cmee to the mammal m effective amount of at least one compound of Formula (la) or (¾), or a pharmaceutically acceptable salt or solvate thereof

In one as ect, LP A and LPA receptors (& g. LPAi ) are involved in the

pathogenesis of osteoarthritis (Kotan! si al. Hum Moi . Cfewef 281B, i f, 1790-1797). In one aspect presented herein is the use of a compound ofFormula (la) or fib), or a pharmaceutically acceptable salt or solvate thereof in the treatment or prevention of osteoarthritisin a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

In one aspect, LPA receptor (e.g. LPA·, LPAy) contribute to the pathogenesis of rheumatoid arthritis (Zhao et «/, Mol Pharmacol, 2O0S, 77(2), 587-6CM)), In one aspect, presented herein is the use of a compound of Formula (la) or (Tb), or a pharmaceutically acceptable sal t or sol vate thereof in the treatment or prevention of rheumatoid arthritis in a mammal comprising administering at least once to the mammal an effective amount of at least one compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

la one aspect, LPA receptors (eg. LPA-j) contribute to adipogenesis, (Simon eife, JBiol Chem 2005, voL 280, no 15, p.14656), In one aspect, presented herein i the use of a o pound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof in the promotion of adipose tissue formation in a. mammal comprising administering at least once to the mammal an effective amount of at least one compoun of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof a. In Yitm Assays

The effectiveness of compounds of the present invention as LPAi inhibitors can. be determined in m LPAs functional antagonist assay as follows:

Chinese hamster ovary cells overexpressing human 1-PAi were plated overnight (15,000 eells/wcB) in polv-D-lysine coated 384-well microplates (Greiner bio-one, Csi#?8i946} ¾ DMEM/F12 medium (Grheo, Cat#l 1039). Following overnight cnliure. cells were loaded with calcium indicator dye (AAT Bioquest Inc, Cal# 3400! } for 30 minutes at 3? ^C C. The cells were then equilibrated to room temperature for 30 minutes before the assay lest compounds solnbiiiged in DMSO were transferred to 334 well non- binding surface plates (Corning _» Cat# 3:575) using the Labcyte Echo acoustic dispense and diluted with assay buffer [IX HESS with ealeium/magpesittm (Gtbeo Cat# 14025- 092.1, 20 tnM HEPES (Gibed Cat# 15630-080) and 0.1% fatty acid free BSA (Sigma Gat

A92051) to a final concentration of 0 5% DMSO. Diluted compounds were added to the cells by FDS86000 (Hamamatsu) at final concentrations ranging from 0,08 nM to 5 m.M. and were then incubated for 2(1 min at room temperature at which time LPA (Avanti Polar lipids Gat#8S7130C) was added at final concentrations of 10 nM to stimulate the cells. The compound 1C··;;· value was defined as the concentration of test compound which inhibited 50% of the calcium flux induced by LPA alone. lCso values were determined by fitting data to a 4-parameter logistic equation (GraphPad Prism, San Diego€A). b In Vivo Assays

LPA Challenge with plasma histamine evaluation.

Compound is dosed orally p.e. 2 hours to CD-I female mice prior to the LPA challenge. The mice are then dosed via tail vein { IV) with 0.15 mL of LPA In 0.1.84BSA/ 1035 (2 pg/pL) Exactly 2 minutes following the LPA challenge, the mice are euthanized by decapitation and the trunk blood is collected. These samples are collectively centrifuged and .individual 75 pi. samples are frozen at ~20°€ until the time of the histamine assay. The plasma histamine analysis was run by standard EIA (Enzyme Immunoassay) methods. Plasma samples were tha ed and diluted 1 ;30 in 0. ! % BSA m PBS The El A protocol for histamine analysis as outlined by the manufacturer was; followed (Histamine BIA, Oxford Biomedical Research, EA#31}

The LP.A used in the assay is formulated as follows; LPA (1 -oleoyl-d-hydroxy-sn- glyeerom -phosphate (sodium salt}, 857130P, Avanti Polar Lipids) is prepared in

0.1¾BSA/PBS for total eonee raflon of 2 gg/pE 13 mg of LPA is weighed and 6 5 n l, CU%BS:A added, vortexed and sonicated for --4 hour until a clear solution is achieved

¥ PHARMACEUTICAL COMPOSITIONS, FORMULATIONS AND

COMBINATIONS

In some embodiments, provide is a hannaeeuiicn! composition comprising a therapeutically effective amount of a compound of Formula (la) or (lb), or a

pharmaceutically acceptable sail or solvate thereof. In some embodiments, the pharmaceutical composition also contains at least one pharmaceutically acceptable inactive Ingredient

In some embodiments, provided Is a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (la) or ( b), or a

pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable inactive ingredient. In one aspect, the pharmaceutical composition is formulated for Intravenous injection, subcutaneous injection, oral administration, inhalation, nasal admini tration, topical administration, ophthalmic administration or otic administration. In some embodiments, the pharmaceutical composition is a tablet a pill, a capsule, a liquid, an inhalant, a nasal spra solution, a suppository, a suspension, a gel, a colloid, a dispersion, a suspension, a solution, an emulsion, an ointment a lotion, an eye drop or an ear drop.

In some embodiments, the phannaceudca; composition further comprises one or more additional therapeutically active agents selected from; corticosteroids (&g., dexuraethasone or fluticasone), !mmunosuppresants (e.g. , tacrolimus & pimecroii us), analgesics, anti -cancer agent, anil-inilammaforks, chemokine receptor antagonists, bronehodliators, lei&otxlene receptor antagonists {e.g„ montelukasi or zaiMukast).

ieukotriene formation inhibitors, moaoacylglycerol kinase inhibitors, phospholipase A.t inhibitors, phospholipas inhibitors, and lysophospho lipase D (SysoPifD) inhibitors _» aufofaxin ihhibitors, decongestants, antihistamines (eg , lomtidine), roucolylies, anticholinergics, antimssives, expectorants. aBti- fcctiws (eg. , fhsMie acid, particularly for treatment of atopic dermatitis), anti-flmgals (c.g , dotriazoie, particularly for atopic dermatitis), anti-fgB antibody therapies (e, , oniahznaiafe), (k?. adrenergic·: agonists (eg. , albuterol or salmeterol), other PGD2 antagonists acting at other receptors such as DP antagonists, PDB4 inhibitor (Eg·, cilorail&st), drugs that modulate cytokine production, e.g _r TACK inhibitors, drugs that modulate activity of Th2 cytokines IL-4 & IL-5 (dg., blocking monoclonal antibodies & soluble receptors), PPARy agonists (a. , rosigHiazone and piogliianone), 5 -lipoxygenase inhibitors (eg;, zileuton).

In some embodiments, the pharmaceutical composition ihriher comprises one or more additional antl-fibrotic agents selected item pixfenidone, mntedanib, thalidomide,car mah, FG-3019, Ifesolim nab, interferon alpha, feeithinized superoxide dismutasc, simtuzumab, taaxisertib, tralokinu ab, hu309, AM- 152, IFN~ gamma- l b, I -OOl, IPEM- 151, PXS-2S. pentoxiiyd!iiie/H-aoety!-cysteine, penioxlfyll e/vifamm E, sa!butampl snffate, [Sar9,Met(02}l 1 J-Sobstance P, pentoxifylline, mercaptamine bhartrale, obeticholic acid, aramehol, G F~505 _> olcosapentaenoie acid ethyl ester, metformin, msireleptin, muiomanab-CD3, oliipraz, IMM-124-E, Mfe-4074, PX-102, RO-5093151.

In some embodiments, provided is a method comprising administering a. compound of Formula Ha- or (lb) or a pharmaceutically acceptable salt or solvate thereof, to a. human with a LPA dependent or LPA-xnediated disease or condition. In some embodiments, the human is already being administered one or more additional therapeutically active agents other than a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof In some embodiments, the method further comprises administering one or more additional therapeutically active agents other than a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

In some embodiments, the one or more additional therapeutically active agents other than a. compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof are selected from; corticosteroids (c.g,. dexamethasone or fluticasone), hu uuosuppresants (e,g. , ticrolimn & pimeero linn; _' ;·, analgesics, anti-cancer agent, anti-inflammatories, che. ok.ine receptor antagonists, brouchodilato.rs, leukotiiene receptor antagonists (e. , montelufcast or xaiu iuka-t f leokotriene formation inhibitors.. monoaeylgtycerol kinase inhibitors, phospholipase AT inhibitors, phospholipase ,½ inhibitors, and lysophospho lipase D (lysoPLD) Inhibitors _* autotaxk inhibitors, decongestants, antihistamines (g.g. , iorabdme), muco!ytks, anticholinergics, antitnssives, expectorants, anii-tnlectives (eg , fusidic acid, particularly for treatment of atopic dermatitis), autr-fungals (e g. , eiotxlazoie, particularly for atopic dermatitis), anli-IgB antibody therapies (eg , omalizurnab), f$~2 adrenergic agonists ( g , albuterol or salffieiero!), other PGD2 antagonists acting at other receptors such as DP antagonists, PDE4 inhibitors (eg , cilormlast), drugs that modulate cytokine production, e g. TAGB inhibitors, drugs that modulate activity of Th2 cytokines 11,-4 & IL-S (e g . Mockingmonoclonal antibodie & soluble receptors), PPA&y agonists {e,g. , rosiglitazone and ploglitazone}, 5 -lipoxygenase inhibitors (e.y , Etleuion),

in some embodiments, the one or more additional therapeutically active agents other than, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof are other an i -b hr otic agents selected froia pirfenidone, rdntedan!b, thalidomide, earlumab, FO-30I9, fresoiiniumab, interferon alpha, ledih ized superoxide dis utase, sinitnznniab, tanzisarllb, tr&lok umab, hu3G9, AM-152, 1FN -gamma- lb. !W~ 001 , PRM- 15 L PXS-25, penioxiMlme/N-aeetyi-cysteine, pentoxify I line/vitaniin E, saibuiamol suliate, [Sar9,Met(02)l!]~Substance P, pentoxifylline, mercaptamme bitartrate, obeiicholic cid, ata chol GFT-505, elcosapentyi ethyl ester, metformin, metreleptin, rouromonab-Cm oitlpraz, ilVlM-124-E, MK-4074, PX-102, RO-5093151, in some embodiments the one or more additional therapeutically active agents other than a compound of Formula f la) or ( h), or a phar aceutically acceptable salt or solvate thereof, are selected from ACE inhibitors, ramiprll, All antagonists, rtbesartan, anti-arrythmics, droned&rone, PPARct activators, PPARy activators, piogiitaxone, rosiglitazone, prostanoids, endotbclin receptor antagonists, elasta.se inhibitors, calcium antagonists, beta blockers, diuretics, aldosterone receptor antagonists, ep!erenone, renin inhibitors, rho kinase inhibitors, soluble gnanylaie cyclase (sGC) activators, sGC sensitizers, PDE inhibitors, P.DB5 inhibitors, NO donors, digitalis drags, ACE/NEP inhibitors, statins, bile acid reuptake inhibitors, PDOF antagonists, vasopressin antagonists, aquarelles, NHE1 inhibitors. Factor X.a antagonists. Factor XII la antagonists, anticoagulants anft-dirombotics, platelet inhibikus. profibro!tics _» thrombin · acti vatable fibrinolysis inbibitms (TLί- h. PAM inhibitors, ummar s. heparins, thromboxane antagonists, serotonin antagonists, COX Inhibitors, aspirin, therapeutic antibodies, GHIb/nia antagonists, ER antagonists, SERMs, tyrosine Mnase inhibitors, RAF kinase inhibitors, p38 MARK inhibitors, pirfenidone, niulii-kinase inhibitors, mnted&mb, sorafenib.

In some embodiments, the one or more additional irerapemieahy active agents other than a compound of formula a) or (lb), or a pharmaceutically acceptable salt or solvate thereof, are selected from Gretnlim! mAh, PAl-i mAh, Proroedfor (PRM-451; recombinant hnntan Pe»Umin~2); FGF21, TGII/b antagonists, anbb & avj) pan- antagonists; FAK inhibitors.. T02 Inhibitors, LOXL2 inhibitors, N0X4 inhibitors, MGAT2 Inhibitors, GPR120 agonists

Pharmaceutical formulations described herein are admMstrahle to a subject In a variety of ways by multiple administration routes, including but not limited to, oral, parenteral (eg;, intravenous, subcutaneous, intramuscular), iniranasal, buccal, topical or trausdermal administration routes. The pharmaceutical formulations described herein include , but are not limited to, aqueous li qui d lspersi ons, seiAetmtisIf ing dispersions solid solutions, liposomal dispersions, aerosols, solid dosage farms, powders, immediate release formulations, controlled release formulations, last melt formulations, tablets, capsules, pills, delayed release formulations, extended release formulations, pulsatile release formulations, multiparticulate formulations, and mixed Immediate and controlled release formulations.

In some embodiments, the compound of Formula (la) or (lb), or a

pharmaceutically acceptable salt or solvate thereof is administered orally.

in some embodiments, foe compound of Formula (la) or (lb), or a

pharmaceutically acceptable salt or solvate thereof, is administered topically. In such embodiments, the eompound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, Is formulated into a variety of topically admirustrable compositions, such as solutions, suspensions, lotions, gels, pastes, shampoos, scrubs, rubs, smears, medicated sticks, medicated bandages, bairns, creams or ointments. Such pharmaceutical compounds can contain solubilizers, stabilizers, tonicity enhancing agents, buffers and preservatives. In one aspect the compound of Formula (la) or (lb), or pharmaceutically acceptable salt or solvate thereof is administered topically to the skin. In another aspect, the compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, is administered by inhalation. In one embodiment, the compound of Formula (la) or (Ih), or a pharmaceutically accepta le salt or solvate thereof, is administered by inhalation that directly targets the pulmonary system

In another aspect, the compound of Formula (la) or (3 b). or a pharmaceutically acceptable salt or solvate thereof, is formulated for mtranasal sdnaaisixatfon, Such Ibrmulatxoiis include nasal sprays, nasal mi sts, and the like.

In another aspect, the compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, is formulated as eye drops.

hi another aspect is the use of a compound of Form ula (la) or (3b). or a

pharmaceutically acceptable salt or solvate thereof, in the manufacture of a medicament for treating a disease, disorder r conditions in which the activity of at least one LP.4 receptor contributes to the pathology and/o symptoms of the disease or condition. In one embodiment of this aspect, the LFA is selected from LFAs, LPA _& LFAs, LPA^, LPAsand LPA*. In (me aspect, the LFA receptor is LFAi In one aspect the disease or conditio is any of the diseases or conditions specified heroin.

In any of the aforementioned aspects are further embodiments in. which; (a) the effective amount of the compound of Formula (la) or (lb), or a phar aceutically acceptable salt or solvate thereof) Is systemic-ally administered to the mammal; and/or (h) the effective amount of the compound is administered orally to the mammal; and/or (c) the effective amount of the compound is I:nira.vcnousIy administered to the mammal; and/or (d) the effective amount of the compound is administered by inhalation; and/or (e) the effective amount of the compound -is administered by nasal administration; or and/or if) the effective amount of the compound is administered by injection to the mammal; and/or (g) the effective amount of the compound is administered topically to the mammal; and/or (hi the effective amount of the compound is administered by ophthalmic administration; and/or (i) the effective amount of the compound is administered rectal!y to the mammal; and/or (j) the effective amount is administered non-systemieali or locally to the mammal

In any of the aforementioned aspects arc farther embodiments comprising single administrations of the effective amount of the compound, including farther embodiments in which (!) the com ound is adn nistered once- (it) the compound is administered to the mahimal multiple times over the span erf one day; (hi) eoutiunally; or (iv) continuously

In any of the aforementioned aspects are further embodimeats comprising multiple administrations of foe effective amount of the compound including further embodiments in which (I) the compound is administered continuously or intermitently; as in a a single dose; (ii) the time between multiple administrations is every 6 hours; (iii) the compound is administered to the mammal every S hours; (iv) the compound is administered to the mammal every 12 hours; (v) the compound is administered to foemammal every 24 hours. In further or alternative embodiments the method comprises & drug holiday, wherein the administration of the compound Is temporarily suspende or the dose of the compound being administered is temporarily reduced; at the end of the drug holiday , dosing of the compo und is resumed. In one embodiment the length of the drug holiday varies from 2 days to I year.

Also provided is a method of inhibiting the physiological activity of f, PA in a mammal comprising administering a therapeuticall effective amount of a compound of

Fomiula (la) or (lb) or a pharmaceutically acceptable salt or solvate thereof to the mammal in need thereof

In one aspect provide is a medicament for treating a LP.4-dependent or LPA~ mediated disease or condition in a mammal comprising a therapeutically effective amount of a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof

In some eases disclosed herein is the use of a compoun of Formula (la) or (lb), or a pharmaceuticall acceptable salt or solvate thereof in the manufacture of a medicament fin foe treatment of a LPA-dependent or LPA-med ted disease or condition

In some cases disclosed herein is the use of a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof in the treatment or prevention of a LPA-dependent or LPA-mediated disease or condition.

In one aspect, is a method for treating or preventing a LPA-dependent or LPA- mediated disease or condition in a mammal comprising administering a therapeutically effective amount of a compound of Formula (la) or (lb), or a phar aceutically acceptable salt or sol vate thereof In one aspect, LP A-depeude.ot or LPA-mediated d seases or conditions include, but are not limited to, fibrosis of organs or tissues;, scarring, liver diseases, dermatological conditions, cancer, cardiovascular disease, respiratory diseases or conditions,

inflammatory disease gastrointestinal tract disease, renal disease, urinary traet-associaied disease, inflammatory disease of lower urinary tract, dysuria, frequent urination, pancreas disease, arterial obstruction, cerebral Infarction, cerebral hemorrhage, pain, peripheral neuropathy, and fibromyalgia.

In one aspect, the LPA-dependent or LPA-mediated disease or condition is a respiratory disease or condition In. some embodiments, the respiratory disease or condition is asthma, chronic obstructive pulmonary disease (COPB), pulmonary fibrosis, pulmonary arterial hypertension or acute respiratory distress syndrome.

In some embodiments, the LPA -dependent or LPA-mediated disease or condition is selected from idiopathic pulmonary fibrosis; other diffuse parenchymal long diseases of different etiologies including iatrogenic drag-induced fibrosis, occupational and/or environmental induced fibrosis, granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease, alveolar proteinosis, !angerhans cell

granulomatosis, iymplrangioleioniyomatosis, inherited diseases (Hermansky-Pudlak Syndrome, tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial Interstitial lung disease); radiation induced fibrosis; chronic obstructive pulmonary disease (COPD); scleroderma; bleomycin induced pulmonary fibrosis; chronic asthma; silicosis; asbestos induced pulmonary fibrosis; acute respiratory distress syndrome (ARDS); kidney fibrosis; ubuloi tersfitiuin fibrosis; glomerular nephritis; focal segmental glomerular sclerosis; IgA nephropathy; hypertension; Alport; gut fibrosis; liver fibrosis; cirrhosis; alcohol induced liver fibrosis; toxic/drug induced liver fibrosis;

hemochromatosis; nonalcoholic steatobepafifis (NASH); biliar duct injury; primary biliary cirrhosis; Infection induced liver fibrosis; viral induced liver fibrosis and autoimmune hepatitis; corneal scarring; hypertrophic scarring; Doputren disease, keloids, cutaneous fibrosis; cutaneous scleroderma; spinal cord injury/fibrosis; myelofibrosis; vascular restenosis atherosclerosis; arteriosclerosis; Wegener's granulomatosis;

Peyronie's disease, chronic lymphocytic leukemia, tu or metastasis, transplant organ rejection, endometriosis neonatal respiratory distress syndrome and neuropathic pain. In one aspect the LPA-dependent or LPA-mediated disease ox condition isinsc ibe herein.

in one aspect, provided is a method for the treatment ox revention of organ fibrosis in a mammal comprising administering a therapeuticall effective amount of a compound of Formula. (la) or (Il>) or a pharmaceutically acceptable salt or sol vate thereof to a mammal in need thereof

in one aspect, the organ fibrosis comprises lung fibrosis, renal fibrosis, ox hepatic fibrosis

l one aspect, provided is a method of improving bag function in a mammal comprising administering a therapeutically effective amount of a co poha of Formula (la) or (lb), or a pharmaceutically accep table salt or sol vate thereof to the m ammal i need thereof In one aspect, the mammal has been diagnosed as having lung fibrosis

In one aspect, compounds disclosed herein are used to treat idiopathic pulmonary ribrosis (usual Interstitial pneumonia) in a mammal

In some embodiments, compounds disci used herein arc used to treat diffuse parenchymal interstitial long diseases in mammal: iatrogenic drug induced,

oeonpatiooal/environrnenral (Parmer lung), granulomatous diseases (sarcoidosis, hypersensitivity pneumonia), collagen vascular disease (scleroderma and others), alveolar proteinosis, langerhaus cell granulonmatosis, lyxnphangiolelomyomatosis, Hexmairaky- fiud!ak Syndrome, Tuberous sclerosis, neurofibromatosis, metabolic storage disorders, familial interstitial lung disease.

In some embodiments, compounds: disclosed herein are used to treat post-transplant fibrosis associated with chronic rejection in a mammal: Bronchiolitis obliterans for long transplant

In some embodiments, compounds disclosed herein arc used to treat cutaneous fibrosis in a mamma!: cutaneous scleroderma, Dupuytren disease, keloids.

In one aspect, compounds disclosed herein are used to treat hepatic fibrosis with or without cirrhosis in a mammal; toxic/drag induced (hemochromatosis), alcoholic liver disease, viral hepatitis (hepatitis B virus, hepatitis C virus, I!CV), nonalcoholic liver disease (NAFLD, MASH), metabolic and auto-immune disease.

In one aspect, compounds disclosed herein are used to treat renal fibrosis in a mammal: tubuloioiersiithmi fibrosis, giotnerniar sclerosis. la any of the aforementioned aspects involving the treatment of LPA dependent diseases or conditions are further embodiments comprising administering at least one additional agent in addition to the administration of a co pound having the structure of Formula a) or (lb), or a pharmaceutically acceptable salt ox solvate thereof- 1» various embodiments, each agent is administered in airy order, including simultaneously

lit any Of the embodiments disclosed herein, the mammal Is akuman.

In some embodiments, compounds provided herein are administered to a human.

In some embodiments, compound p ovided herein ate orally administered la some embodiments, compounds provided herein are used as antagonists of at

10 least one LPA receptor. In some embodiments, compounds provided herein are used for inhibiting the activit of at least one LPA receptor or lor the treatment of a disease or condition that would benefit front inhibition of the acti vit of at least one LPA receptor.

In one aspect the LPA receptor is LPA*.

In other embodiments, compounds provided herein are used for the formulation of

15 a medicament for the inhibition of LPA] activity.

Articles of manufacture, which include packaging material, a compound of Formula (la) or (lb), or a pharmaceutically acceptable salt or solvate thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxtde,

>0 pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or

pharmaceutically acceptable solvate thereof is used for inhibiting the activity of at least one L PA receptor or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from inhibition of the activity of at least one LPA receptor, are provided

VI. GENERAL SYNTHESIS INCLUDING SCHEMES

The compounds of the present invention can be prepared in a number of ways known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic (5 methods known m the art of synthetic organic chemistry, or by variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limite to, those described below. The reactions are performed in a solvent or solvent mixture appropriate to the reagents an materials employed and suitable for the transformations being ; effected. It will be understood by those- skilled in the ait of organic synthesis that the functionality present on the molecule should be consistent W th the transformations proposed . This will sometimes require a judgm ent to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the in vention.

it will also be recognize that another major consideration in the planning of any synthetic route in this held is the judicious choice of the protecting group used for protection of the reactiv functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene et ah, ( Protective Groups in Organic Synthesis, Fourth Edition, Wiieydnterseknce (2006)).

The compounds of formula {&) or (lb) may he prepared by the exemplary processes described in the following schemes and working examples as well as relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions appear herein after and in the working examples.

Protection and deprotection in the processes he!ow may be carried out by procedures generally known i the art (see, for example, Wats, P.G.M., Greene 's Protective Groups in Organic S nthesis 5 th Edition. Wiley (2014)). General methods of organic synthesis and functional group transformations are found In: Trost, B M el al, Eds.,

Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Pergamon Press, New York, NY (1991); Smith, M B et aL March's

Advanced Organic Chemistry: Reactions, Mechanism , and Structure, 7th Edition, Wiley, New York, NY (2013); Katritzky, A.R et al, Eds , Comprehensive Organic Functional Group Transformations IT, 2nd Edition, Elsevier Science Inc , Tarrytown, NY (2004); Laroek, R.C., Comprehensive Organic Transformations,. 2 Edition, Wiley-VCIL New York, NY (1999), and references therein.

Scheme 1 describes the synthesis of isoxazole-axole aryl(heteroaryl)eycl.ohe yi acids 15. A 4-halo (preferably bromo) phenyl or axine (e,g pyridine) benzoic acid 1 is converted to the corresponding acid chloride (e.g. with SQCk o oxa!yl chloride/ catalytic DMF) This acid chloride Intermediate is reacted with an appropriate p-enammo-ester 2 followed by condensation with kydroxylaaune to furnish the corresponding S~ haio(heiem}aryl~isoxazole 4-carboxyMe ester 3. Deproteetion of the ester 3 followed by reduction of the resulting acid (e.g, directly with diborane or by a 2-step procedure by reacting the acid with an alkyl ehlorofomtaie followed by reduction with e.g. NaBfR at low temperature) and protection of the resulting alcohol pro vides the S-halo(hetero)aryl- isoxaxole protected alcohol 4 Reaction of the haloaryl- or halohetetoaryl-isoxaxoies 4 witb pinaeol diboron ate in the presence of tin appropriate palladium catalyst (e.g, Ishiyama, T. et al, ,/. Org Chem 1995, §0, 7508-7510) piovid.es the corresponding pinacol borona e 5, which is then oxidized with hydrogen peroxide to give the

corresponding phenol or hydroxyheteroarene 6 (Fuk noto, S et ai, WO 2012137982). Reaction of phenol foydroxyheteroarene 0 with a 3 -hydroxy eydohexyl ester 7 under Miisonohu reaction conditions (Kunrara Swamy, K. Cheat Rev., .201)9, 70.9, 2551- 2651 } furnishes the corres onding Isoxazole cyeioslhy! ether ester 8. Deproteetion of the hydoxymethyltsoxazole 8 provides the cyclohexyl ester Isoxazole alcohol 9. Isoxazole alcohol 9 is then reacted with PBrs (or another mild hronbnating agent such as

CBnj PhsF) to give the corresponding bromide 10 Displacement of isoxazole bromide 10 with NaNs (or other azide equivalent reagents) gives isoxaxole azide 11 which undergoes reduction fe.g Staadinger reduction with PhsP/water) to afford isoxazole amine 12.

Isoxazole amine 12 is then reacted with an appropriate halo-azole 13 in the presence of an appropriate base (nucleophilic aromatic substitution reaction) or via Pd~eata!yzed a ination to give isoxazole amino-azole cyeiobexyi esters 14, which then undergoes ester deproteetion to give the desired isoxazole-axole aryloxy eycioalkyl acids 15.

Scheme 1

1) SQ<¾ or (COCOs

Scheme 2 describes an alternative syntheti e route to the ammo-ary i/heteroaryl isoxazoIe-aryloxY cy ohexy! adds 15. Reaction of the am o -azine 16 with the bromide 10 either in the presence of base (g g _> NaH, e|e. _s ) or under transition meinl-eatalysia conditions (e.g Pd-ligand-mediated) affords e amino-az e methyl Isoxazole-aryloxy cy ohexyi ester 14. Subsequent ester deprotection of eydo exyi ester 14 provides die desired asiino-azme isoxazole-aryidieteroaryi-oxy eydohexyl acids 15

Sche e 2

: ⁱ

Scheme 3 describes ait alternative synthesis of isoxazoie-axole aryfoxy-cydohexyl acids I S. The liafo-isoxazole 4 is depOiecied to give the isoxaxole alcohol, which is then converted to the corresponding isoxazole bromide 17 (with a hram atmg agent such as

OBn or CBia/Fh.iP) _; and subsequently to the isoxazole amine .18 (via. a 2-step sequence as in Scheme 1 with Nahh displacement of the bromide, followed by a Standings? reduction

15 of the aside prod uct [PhsP/Hj ()]) fdsoxnxole amine 18 is then subjected to either a base- mediated reaction or a iranshion-metabeatalyzed cross-coupling reaction (e g. palladium- mediated) with a halo-azole 13 to furnish the isoxazole ammo-azoic 19 Conversion of the bro o-aryl/heteroaryl woxa/ole 1 to the corresponding hydroxy-aryl/heteroaryl

triaz.ole 20 is achieved via the corresponding botoaaie using the 2 stop sequence

20 [B(pin);xPd-eaiJy$is followed by treatment with l¾i¾] described in Scheme 1.

I fydroxyaryi/liydroxyheieroaryi isoxazole 20 is then subjected to a Milsnnobu reaction with hydrox -eyclohexyl ester 7 to give the isoxazole-azole-eydohexyi ester 1.4 followed by deprotection to provide the desired isoxazole-axoie cyclohexyl acids 15 (as described in Scheme 1).

SK Scheme 3

Scheme 4 describes the synthesis of isoxaxoie-ethyhaxo!e eyclohexyl acids 27. The isoxaxole methanol intermediate 9 Is oxidired to the corresponding aldehyde {e.g. Dess-Martin periodi.nane or Sworn oxidation), which is then subjected to an olefinatkm reaction {e.g. Witfig or Peterson oieiinaiion reaction) which provides the isoxaaole terminal olefin 21, Hydroboratio.n of olefin 2.1 at the terminal carbon (e.g, with 9-BBN),followed by oxidative workup, provid.es the corresponding isoxaaole ethyl alcohol 22. Isexannle ethyl alcohol .22 is then reacted with PBrs (or another mild brommatmg agent such as CBw/PfoF) to gi ve the corresponding bromide 23. Displacement of bromide 23 with NaN; _¾ (or other azide equivalent reagents) gives isoxazoie azide 24 which undergoes reduction (e.g, Siaudiuger reduction with I¾P/waier} to afford isoxazoie amine 25. I oxaz ie amine 25 is then reacted with halo-azole 13 in the presence of an appropriate base or via transition meia! (eng. Pd)-eataiyzed aiuination to give the isoxazoie amino- azine 26. which then undergoes ester deprotectioa to give the desired isoxazole-ethj - arni no-azole arvioxv cydohexyl acids 27

Scheme 4

Scheme 5 describes the synthesis of isoxaxo!e amino-azole acids 32 Cyclohexyi ether isoxazoie -alcohol Iff undergoes oxidation to the isoxazoie carboxylic acid 28 (e.g. directly to the acid with pyriditwcm dlehromate or via a 2-step procedure via the aldehyde [S era oxidation or Dess-Martin perlodinane followe by NaClOi oxidation to the acid, e.g !indgretr, B. O.,AM Ghent Scan 1973 27, §88]) Curtins rearrangement of isxe&zoie acid 2% in the presence of t-fmtanoi provides the isoxazoie NH-Boc-earbaraate 29. Deproteetion of the isoxazoie DH-Boc carbamate 29 under acidic conditions

provides the isoxazoie amine 3:0 The isoxazoie-amine 30 then undergoes a transition metal-catalyzed cross-coupling reaction with a halo-azole 13 to give th isoxazoie arnino- azole cyelohexyl ester 31 _» which then undergoes ester deproteetion to give the desired isoxazole-amino ole-aryioxy oyelohexyl acids 32

Scheme 5

Depicted Oxidation Y Rearrangement HBoc

Scheme 6 describes an alternative synthesis of isoxaxole-armrsoazoie aryioxy- eyclohexyl acids 15 Aryl-isoxazole alcohol 9 i oxidized to the corresponding isoxazoie aldehyde 33 (e.g, by Dess-Martin periodmaoe or Swern oxidation). !mine formation (e.g with a Lewis acid such as Ti(OiP:t )Cl) followed by reductive aminaiion (e.g. with

NaBHiOAcb. ref Abdei-Mazid, A.. If. et aL J Or Ckem .1996, 61, 3849-3862 or with aBHsCN) of Isoxazole aldehyde 26 with n appropriately substituted amino-azole 16followed by acid ikpmtectkm prov des die isoxaxole-a inoazole aryfoxjvyelohex-yl adds I S. Scheme 6

VII. EXAMPLES

The following Examples are offered as illustrative, as a partial scope a ! particular embodiments of the invention and are not meant to be limiting of the scope of the invention. Abbreviations and chemical symbols Imve their usual and customary meanings unless otherwise indicated. Unless otherwise indicated, the compounds described herein have been prepared, isolated and characterized using the schemes and other methods disclosed herein or may fee prepared using the same.

As appropria te, reacti ons were conducted under an atmosphere of dry nitrogen (or argon). For anhydrous reactions, DRiSOLV€> solvents from EM were employed. For other reactions, reagent grade or HPLC grade solvents were utilized. Unless otherwise stated, all commercially obtained reagents were used as received.

Microwave reactions were carried out using a 400 W Blotage Initiator instri ient in microwave reaction vessels (0,2 ~ 0 5 mL; 0 5-2 mL; 2 - 5 mL; 10-20 ml.) under microwave (2.5 GHz) irradiation.

HPLC/MS ami preparatory/analytical HPLC methods employed hi dtaracierixatfon or purification of examples MMR (nuclear magnetic resonance) spectra were typically obtained on Broket or JEOL 400 MH¾ and 500 MHz instruments in the indicated solvents. All chemical shifts ate reported in ppm from tetmmethylsrlane with the solvent resonance as the infernal standard ¾NMil spectral data are typically reported as follows: chemical shift, multi licity (s ~ singlet, hr a ^:::: broad singlet, d -- doublet, dd ⁵⁵⁵ doublet of doublets, t triplet, q ^::: quartet, sen septet, m multiplet, app apparent), coupling constants (Hz), and Integration.

In the examples where ⁵ H MMR spectra were collected in ds-DMSD, a wafer- suppression sequence is often utilized. This sequence effectively suppresses the water signal and any proton peaks in the same region usually between 3 30-3 65 ppm which will affect the overall proton Integration

The term HPLC refers to a. SMmadzirlhgh performance liquid chromatography instrument with one of fo llowing methods; BPLC-l : Sanibe CIS column (4 6 x ISO mm) 3 5 pm, gradient from 10 to 100'% B:A for 1.2 min, then 3 min hold: at 1003» B.

Mobile phase; A: 0,0534 TEA in wateuCl ! CN (95:5)

Mobile phase B; 0.05% TEA in CI*CN:water (95:5)

TEA Buffer pH ^::: 2,5; Flow rate; 1 ink/ min; Wavelength; 254 nm, 220 mm

HPLC--2: XBridge Phenyl (4.6 x 150 mm) 3.5 um, gradient from 10 to 100% B:A for 12 min, the 3 nun hold at 1 0% B.

Mobile phase A: 0.05% TEA in wa:ter:CI¾€N (95:5)

Mobile phase B: 0,05% TEA lit Ci¾€N:waie (95:5)

TEA Buffer pH ~ 2.5; Flow rate; 1 ml,/ min; Wavelength: 254 nm, 220 nm.

HFLC-3: CMraJpak AD-H, 4.6 x 250 mm, 5 mch

Mobile Phase: 30% BtOH-heptane (1 :1) / 70% CO _?

Flow rate 40 ml, /min, 100 Bar, 35 °C; Wavelength: 220 nm

FiPLC-4: Waters Aequlty UPLC BEH Cl 8, 2 1 x 50 mm, 1.7-pm particles;

Mobile Phase A: 5:95€¾CM:water with 10 mM NHaOAc; Mobile Phase B: 95:5€¾CN:waier with 10 mM N¾OAc;

Temperature; 50 °C; Gradient 0-100% B over 3 mm _f then a 0 7S~mm hold at 100% B; Flow: 1.11 roL/im»; Detection: BY at 220 ^" WB _> BPLC-5: Waters Aequity OPLC BEH CIS, 2.1 x 50 mm, I .7~mtk particles;

Mobile Phase A 5.95 C!¾CN:wate with 0.1% TFA;

Mobile Phase B: 95:5 CHiCNtwater with 0.1% TEA;

Temperature: 50 "C; Gradient! 0-100% B over 3 min then a0.7S-rnin hold at 100%

B; Flow: 1.11 mL/min: Detection: t!Y at 220 am

These additional HPLC ant! LCMS methods were also utilised:

Method C: SUNFIRE CIO (4 6 X 150) atm, 3 5 micron column; Flew rate 1 toL/mia; Mobile Phase A: 0.05 % TEA in 95% Water/ 5% ACM; Mobile Phase B: 0.05 % TFA in 5% Water/ 95% ACN; 10% B to 100% B over 25 min, then hold Far 5 min at 100% B; Detection: IJV at 254 and 220 n .

Method D: X-Bridge Phenyl (4 6 X 150) ti e 3,5 micron column; flow rate 1 mL/m ; Mobile Phase A; 0.05 % TFA in 95% Water/ 5% ACN; Mobile Phase B: 0.05 % TFA in 5% Water/ 95% ACN; 10% B to 100% B over 25 min, then hold for 5 min at 100% B;

Detection: UV at 254 and 220 a .

Method E: IQNBT!X XB-G1 S, (3 X 75) mm, 2.6 micron cat n Plow rate: 1 mL/min; Mobile Phase A; 10 mM: HCO2NB in 98% Water/ 2% ACN; Mobile Phase B: 10 mM HOANHB in 2% Water/ 98% ACN; 20% B to 100% B over 4 min, then hold 0.5 rnin at 100% B with flow rate 1.5 niL/min; Detection: UV at 2:20 ran.

Method F: ONETl X XB-CI S, (3 X 75) m¾ 2.6 micron column; Flow rate 1 mL/min; Mobile Phase A: 0.196 HCOOH in 98% Water/ 2% ACN: Mobile Phase B : 0.1 % HCOOH in 2% Water/ 98% ACN; 20% B to 100% B over 4 in , then hold 0,5 min. at 100% B with How rale 1 ,5 niL/min; Detection: UV at 220 nm.

e ethod 0: ACQII!TY BEH 08 (2.1 50) mm, 1.7 micron column; low rate: 0 7 niL/ in; Mobile Phase A: S mrftoi N3¾OAe in 75% Water / 5% ACM; Mobile Phase B: S sixnol N¾OAe 1» 5% Water/ 95% ACN; 20% B to 100% B over 1 min, thee hold for 0 6 in. at 9084 B; Deleciion; IJV at 220: a .

Method H; ACQIJITY BEH Cl 8 (2 1 X SO) mm, 1 7 micron column; Flow rate: 0.7 mL½m Mobile Phase A; 5 mnfol NiitOAe its 95% Water / 5% ACN; Mobile Phase B; 5 mmol NFBOAe in 5 Wdier/ 95% ACN; 20% 8 to 1 0% B over l mitt, then hold for 0 6 min, ai 90% B; Detection: IJV at 220

Method 1: ACQUITY BEH C 18 (3 X SO) mm. 1.7 micron column; Flow rate; 0 7 mB/min; Mobile Phase A: 5 mmol NlEOAe in 95% Water/ 5% ACN; Mobile Phase B: 5 mmol NBA c in 5% Water/ 95% ACN; 20% B to 100% B over I mi , then hold for 0 6 min at 90% B; Detection: IJV at 220 nm.

Method I; ACQIJITY BEH€18 (2. I X 50) mm, 1 7 micron column; Flowrate: 1.1 mL/min; Mobile Phase A: 0.1 A, T FA in 95% Water/ 5% ACN; Mobile Phase B: 0.1% TEA in 5% Water/ 95% ACN ; 0% B to 98% B o ver 1.6 min, then hold for 0 6 min. at 90% B; Detection : IJV at 220 nm,

Method K.r Ascends Express CIS (2.1 X 50) mm, 2.7 micron column; /Flow rate: L i talJmm Mobile Phase A; 0.1% TFA in 95% Water/ 5% ACN; Mohiie Phase B: 0.1% TEA in 5% Water/ 95% ACN; 0% B to 100% B over 4 min, Detection: 1.1 V at 220 nm. Method L; Zorbax (3 X 50) nrm. 1.7 micron column; Flow rate 1.5 mL/min; Mobile Phase A: 10 mmol NECOAc in 95% Water/ 5% ACN; Mohiie Phase B: 10.mmol NFBOAe i 584 Water/ 95% ACN; 3056 B to 100% B over 4.6 min, then hold for 0.4 min at 30% B; Detection: IJV at 220 nm, Method M; X-Bridge BEH Cl 8 (2, 1 X 50) mm, 2.5 micron column; Bow rate 0.5 mL/min; Mobile Phase A: 5 mmol NlEOAe in 95% Water/ 5% ACN; Mobile Phase B: 5 mmol NRiOAc in 596 Water/ 95% ACN; 20% B to 9096 B over 2 min; Detection: LA? at 220 nm. Method 19: Rorbax SBC .18 (4 6 X 50) , 5 micron column; Flow rate 1.5 mL/min; Mobile Phase A; 10 mmol NHAlAc in 98% Water/ 2% ACN; Mobile Obese B: It ⁾ oimrd NfBOAe in 2% Water/ 98% ACN; 30% B to 100% B over 4.6 min, then hold lor 0 4 in. at 3053 ¾ - Detection: UV at 254 am.

Intermediate 1. (1 S,3 S)-isopropyI 3X444~(IiydtO:xymelhy!T3 neibylisaxaxob5~

>d)phenoxy}c yclo-h ane- 1 -carboxyl sie

1 A. (5~(4~braim phenyl)-3-met ylisexazol 4*yi) etfease;

To a solution of 544”bro ophenyI)-3~metliy!isoxazoie-4-carboxyiic acid

(synthesized according to the procedure described in US2011/82164 Al, 2.0 g, 7.09 mmol) in THF (50 mL) was added BH-r THF (28 4 snL of a 1 M solution in THF, 28.4 mmol) poctiomvise a 0°C and the solution was allowed to warm - RT and stirred overnight at RT. The reaction mixture was carefully quenched with ]¾(), acidified with IN aq. HCI (SO mL), stirred for 1 h at RT, then was extracted with BtOAc (2x) The combined organic extracts were washed with !¾0, brine, dried (MgSCV), and

concentrated m vacuo. The residue was chromatographed (SiC ; continuous gradient .from 35-75% EtOAc in Hexanes) to give the title compound (1.65 g, 87 % yield) as a white solid. LCMS. ( 1THG - 268. ¾ N R (€IX¾ 400 MHz) 6 7 73 - 7.64 (m, 4H), 4 66 (d, JAM Hz, 210, 2.42 (s, 3B). intermediate I B 5~(4-bromophenyl}-3-nwiiwT4~i(CteitahydK>-\2H~p¥ran~2- d)oxy}metiwl) isoxszote

To a solution of Intermediate 1 A (626 mg, 2 33 mmol) m C¾Qh (10 mL) was added 3 ₅ 4 dihydro-2H~pyran (0.64 ml., 7 0 mmol) and PFTS (29 mg, 0.12 mtaol), After stirring overnight at RT, the mixture was: quenched with satd aq. NaHCQs and extractedwith EtOAe (2x). The combined organic extracts were washed with PbO, brine, dried (MgSO _f ), and concentrated in vacuo The residue was chromatographed (SiOct continuous gradient from 35-100% EtOAe/Hexanes) to give the title compound (81 1 g, 99 % yield) as a white solid LEMS, [M+E† - 358. ¾ MR (500 M¾ QDCB) 6 7.82 ·· 7.55 (m, 4H), 4.69 (m 1H), 4 65 (m !$¾ 4.46 (m, IB), 3.8? (ra, IB), 3.54 (m, 1H), 2,37 (a, 3H), 1 86 - 1 55 (m, 6H), Intermediate 1€. 4 (3-met ^: hyl-4~(((tefrahy ro-2H-pyra«~2-yl oxy)mefhyl)isoxa¾oHS- yBphenoI

To a solution of R OB (2 70 g, 48,1 mmol) in l¾0 (50 L) were added

Intermediate IB (5 65g, 16.0 mmol) and I,4~dioxane (SO mid an the solution was degassed with N2, wBtiXphos (0.545 g, 1.28 mmol) and Pt¾<iba)3 (0.294 g, 0.321 mmol) were added and the suspension was degassed with Kb, then was stirred at 90 overnight. The reaction mixture was cooled to RT, acidifie with IN aq. HQ and extracted wit EtOAe (2x) The combined organic extracts were washed with l¾0, brine, dried

(MgSCfi), and concentrated in vacuo. The residue was chromatographed (SiOa; continuous gradient fiom 25-75 % EtOAe/Bexanes) to give the title compound (3.63 g, 78 % yield) as a while solid. LCMS, [MAH]" - 290. ¾ N it (500 MHz, CDC¾) 0 7,72 id, >8 8 Hz, 2% 6.94 (i >g.g I¾ 2H), 4.70 (m, I B), 4.66 (d, 12.4 H¾ IE), 4.48 (d,

A 1 2.4 Hz, IH), 3.89 (m, I H), 3.53 (m, IB), 2.3 (s, 3 H . 1 :88 - 1 .70 (m, 2H), 1.05 - 1.57

(m, 4H)

Intermediate 10. { l 8 5» propyl 3-(4-(3~o:ietiiyT4~(((tetrahydro--2B -pyran--2·- yi)oxy)mefhyi) isoxazol~5~yl) phenoxy)eyclohexaae~l -carhoxyiaie

To a RT solution of intermediate 1C (500 mg, 1.73 mmol), (IS,3R}4sopropy! 3- hydroxy cyclohexanccarfeoxylaie (547 mg, 2.94 mmol), EtsN (0 41 mL, 2,94 mmol) and Fli _.j P (770 mg, 2,94 mol in THF ( 10 mL) was added DEAD (1.34 ml,, 2.94 mmol) portionwise over 15 min, The reaction mixture was stirred at RT for 2 days, then was concentrated In vacuo, dilute with I RC), acidified with IN aq. HO and extracted with EtOAc (2x). The combined organic extracts were washed with BaO, brine, dried

(MgSCfi), and concentrated In vacuo. The residue was chromatographed (SiCh;

continuous gradient from 1.5-70% EiOAe/Hexaoes) to give the title compound (458 mg, 58 96 yield) as a while solid LCMS, [MAH]" = 458. H NMR (500 MHz, CDC¾) 6 7,75 (d, >8 8 Hz. VA 7.03 (d, >8,8 H», 2H), 5)02 (m, IH), 4 ,70 (m, ! HI 4.66 (d, >42.4 Hz, I B), 4 48 (d, >12.4 Bz, IH), 3 88 (m, IH) _* 3.54 fin, 1 H), 2.80 (m, IH), 2 35 (s, 3H), 2.08 - 1.97 (m. 2B i. 1.93 - 1 80 (m, 3Ή) 1.78 - 1.52 (m. 10B), 1.24 (m, 6H), ntermediate 1

To a RT solution of Intermediate 1 i {458 mg, 1.00 mmol) in MeOH (10 ml.) was added PFTS (25 mg, 0.10 mmol). The reaction was stirred at RT overnight, then was heated at 50*€ for 2 and cooled to RT. The mixture was bssified to pH "7 with satd q. NaHC0 ₃ and concentrated in vacuo. The mixture was diluted with ¾0 and extracted with ElOAc (2x) The combined organic extracts were washed with ¾0 dried (MgSO ), and concentrated in vacuo. The residue was iromaiographed (SiOa; continuous gradient from 1$ _* 70% EtOAc/Eexaues) to give the title compound (263 mg, 70 % yield) as a white solid I CMS, fMTHf - 374. Ί ! NMR (500 MHz, DCh) 87 7 J Ul fofo.8 ¾ 2H), 7,09 (d _> fofo.H !¼ 2P} _: 5.42 (s, 20), 5 (55 (m, !H . 4,74 (m. 1 H), 2.83 (m, 10), 2.45

(s, 31 J 2 04 Cm, 2!¾ 1 92 (rn. 20), L82 - 1.58 ( . 50 K 1-27 (dd. .561 L4 ¾ 00). intermediate 2 (! SJSRBthyl 3~((0 (4~(hydroxymethyI)~3~me(hyiisox:aeol-5-yl)-2- methyi.pyridm-3 -y boxy)

intermediate 2 A. ter/-Buiyt SdS-hiomofommtfrylpyridm-dwbMnnethylisoxaxoieM carboxylate

To a 0°C solution of 5-bromofo-meihyIpico 1 inic acid (3.0 g, 13.9 mmol) in

€.%<¾ (25 mb) and DM (1 mL) under Nj was added SOCb (3 0 ml,, 41 .7 mmol) and the reaction mixture was wanned to RT and stirred at 55 °C for 15 h (no starting material remaining by LCMS at this time). The reaction mixture was cooled to RT and

concentrated in vacuo. The crude acid chloride product was dissolved in THE (10 mL) and a uliuioo of ien-hxtyi 3-^ahy!amino)but~2-c«oate (4.67 g, 27,3 mmol) and pyridine s 2.2 ml, _s 27.3 mmol) in Tl-lb ( 10 ml,} was added slowly at RT. The reaction mixture was stirred at RT for 24 fa (no starting material remaining by LCMS at this point), then was concentrated in vacuo. The residual crude product was dissolved in EiOH (40 mL) and -water (2 mL) and N¾Q¾P¾0 (1.98 g, 41.7 mmol) was added. The reaction mixture was stirred at 60 %I for 15 then was cooled to RT and concentrated in vacuo. Water (SO ml,} was added and the mixture was extracted with EiG Ae (2 x SO L). The combined organic extracts were -washed with ferine (50 ml }, dried (NasSOt) and

5 concentrated' in vacuo. The erode product was chromate paphed (24 g Redlsep^ SiOz column, 10% EtOAe in n-hexanes) to ailbr the tide compound (2,5$ g, 52%, for 3 steps) as an orange liquid. LCMS retention time 1 42 min; m/z 355.0 [M t B f (Method M). ¾ MK (300 Affix, CDCb) 5 5.10 (d, 4 8. K; H¾ IB), 7.67 (d, 7-8.10 Ha, 1 H), 2.73 (s, 3H), 2.48 (fo oBT 1.49 (s, 9H).

t)

Intermediate 2B. 545d3rorrux6~methyipyridm>yl)-3-m.ethyhsdxaxolefo~earboxy iie acid

To a solution of Intemrcdiate 2 A (2.50 g, 7.08 mmol) in CH2CI2 (4 mL) was5 added TFA (3.82 mL, 49.5 mmol) and the reaction mixture was stirred at RT for 15 h, then was concentrated in vacuo to afford the title compound (1.7.3 g, 83%) as a yellow solid. LCMS retention time ~ 0.67 min; m/z 297,3 [M-ffif (Method I) ¾ NM!l (400 MH , CDCb) 6 8.21 (d, 7-8.80 Hx, I H i. 7 92 (d, 3.80 Hx, LB). 2.79 (s. 3H), 2 63 (s, 3H)

0

Intermediate 2C (5-(5-Bromo~6~.methylpyndiTi-2-yl) 3~ ^hyIi80xaxol.-4-yl).methaaol

To a 0°C solution of Intermediate 2B (LS0 g, 5.05 mmol) in THE (80 mL) were added ethyl chiorofonnate (L64 g 15,2 mmol) and EtsN (L4I mL, 10.1 mmol) and the reaction was allowed to warm to RT an stirred at RX for 16 h. The reaction mixture was filtered through Celjte and the filtrate was concentrated in vacuo. The residue was dissolved in. EtOR (15 ml,}, cooled to § °C and aBl-L (0.573 ¾ 15.2 mmol) was added TSse reaction mixture was allowed to warm to RT and stirred at RT tor 1 h, then was quen.ehed with (PC aq. 1 5 N HC1 (50 mL) and extracted with€!¾€¾ (2 x 50.ml). The combined organic extracts were washed with brine (50 mL), dried (NaaSOT) and concentrated in vacuo. The crude product was chromatographed (12 g Redisep* SlGs column, eluting with 20% BiOAc in n-hexanes} to afford the tide compound (1 22 g, 85%) as a white solid. LC S retention time ^:::: L2S ruin mix ~ 283.2 |MTHf (Method

,

To a solution of Intermediate 2C (1.20 g, 4 24 mmol) dioxane (15 mL) was added 3 _; 4~dihydro-2B~pytan (0.463 g, 5.5 mmol) and PFTS (0.533 g, 2 12 mmol). The reaction mixture was stirred at RT for 15 h. then was diluted with water (20 mL) and extracte with EtOAe (2 x 30 mL). The combined organic extracts were wasted with brine (30 mL). dried (NarSOy) end concentrated in vacuo. The crude product was chromatographed (24 g Redisep ' Si(>> column, eluting with 20% EtOAe in hexanes) to give the title compound (.1.30 g, 84%) as a colorless liquid, I, CMS retention time 3 32 min; mfz - 367.2 [MwHJL ¾ NMR. (400 MH¾ CDCL) § ppm 7.91 (d, >8.40 Hz, 1 H), 7.59 (d, 8.40 Hz, 0¾ 5.02 (ABq, 1 1.60 1¾ 2M), 4 $ (h >3.60 ¾ IB\ 4.00 - 4.10 (m IH), 3 80 · 3.95 (m, 1H), 2.70 (s, 311), 2.41 (s, 3B) _? 1.40 - 1.90 (m, 6H).

Intermediate 2E 3 -Methyl -5 (6-methyE5~(4,4 _s S ₅ 5 -tetramethyl- 1 ,3 ,2-dioxahorolam2~ yl)pyridin~2-yl) 4-(((teEahydro-2H-pyrau-2-yi)oxy)methyi)isoxazol:e

To a degassed mixture of Intermediate 2D (1 30 g, 3 54 mmol),

bis{p aeolato)diboron (1 80 g, 7.08 mmol) sad KOAe (0.695 g, 7 08 mmol) in dioxane (40 L) was added lri>is(dipimnyl-pho$p!rinoiie: : ocene pahadium{il)dkhwride- CMeCfe adduct (0 578 g, 0.708 mmol). The reaction mixture was heated at 90 "C far 8 h, then was cooled to RT and filtered through a Celite pad. The Cehie/solids were washed with additional EtOAc (50 mL) aud the combined filtrates wert concentrated in. vacuo to give the title compound (1 25 g 85%) as a colorless oil. This crude product was used in the next reaction without further purification. LCMS retention time - 3.93 min; m z ^::s 415 2 [ t-Hf (Method E)

Intermedlate 2F 2~Methyl-6~(3~methyl-4-(((tehx iydr« 2B-p>Tan-2~

yl)o.xy)meihyl)is0xac.ohS~yi) py:ridisi 3 - qΐ

To a solution of crude Intermediate 2E (1.25 g, 3 02 mmol) in THE (15 ml,) aud wafer (2 mL was added NAB(¾.¾0 (1 .21 g. 12. i ol) and the reaction mixture was stirred at 55 °C for 90 min, then was cooled to RT The reaction mixture was diluted with IhOAe (80 mL), washed with wafer (2 x 50 ml,), dried (Na³SO.i) aud concentrated in vacuo. The crude product was chromatographed (24 g Redisep' ⁸ ’ SiO: column, eliding with 25 % EtOAc in hexane) to afford the title compound (0.78 g _? 85%) as a colorless oil. LCMS retention time ~ 1 14 mm; m/¾ ----- 303.4 |M-H] { Method i). ⁵ H NMR (300 MHx, DMSOfoD 5 19 44 (g lB) _f 7.59 (d, 8.40 Hz, 1H), 7.25 (d ₅ 8.40 Hz, IHh 5.03 (ASq, 12.40 Hz, 21-1), 4.70 (hr. s., 1H), 3.75 - 3.90 Cm, H I), 3.40 0 (m, 1HX 2.39 (s, 3H),

2,29 Is. 3H), 1,35 - 1.80 (m, 6H).

Intermediate 20. (1 S.3S) _" EthyI 3-((2-mefIiyi-6-(3~melhYl--4 (((tetrah.ydro~2H-pwran-2 l)oxy)meihyi) isoxazol -5-yl) pyridin-d-yboxy cyciohexanecarhox lare

To a solution of Intermediate 2P (0,78 g, 2.56 mmol) in toluene (S mL) w s added dbrerTbutyl axediearboxylate (1 .48 g, 6,41 mmol) and PI13P (1 .68 g, 6,41 mmol). The mixture as stirred at RT for 5 ruin, after which (I6,3i?)-eihvl 3- hydroxycyelobexanecarboxylatefOTS g, 4.36 mmol) was added. The reaction. ixture was stirred at 75°C for 20 h, the» was cooled to RT and concentrated in vacuo, The crude product was chromatographed <24 g Si<)¾ elnting with 15 % EtQAe in hexanes) to afford the title compound (0.68 g, 58%) as a colorless oil. LCMS retention time - 1..72 min; mlz - 459.2 fMHTf (Method I). ¾ NMR (400 MHz, CDCb) d 7,67 (d, >8.80 Hz, IH), 7,18 (d, >8.80 Hz, IH), 4,99 <¾ 2H), 4.65 - 4,75 (m, 2H), 4.11 (¾ >7,20 Hz, 2H), 3.88 - 3.98 Cm, 1H), 3.45 - 3.58 (m, 1¾ 2.75 - 2.85 (m, I H), 2,51 (s, 3H), 2.38 (s, 3B), 2.00 >.15 (m, 1.H) 1.80 - 2,00 (m, 3B), 1.40 - 1.75 (m, 10B), 1.23 (t _s >?.20 Hz, 3H),

Intermediate 2

To a solution of Intermediate 2G (680 mg, 1.48 m oi ) in MeOH <5 mi.) was added pTsOiLibO (141 mg, 0.741 mmol) and the reaction mixture was stirred at RT for 3 h, then was eonecoirated in vacuo. The crude product was chromaiographed (12 g Redisep ^' * ^' SiOs column, «luting with 30 % EtOAc in hexanes) to give the title compound <340 mg ₅ 61 %) as a colorless oil LCMS retention time - 1.38 min; m z 375.5 [M4-H _. (Method 1). ¾ NMR (400 MHz, CDCb) 6 ppm 7 78 01, ,6 8.40 Hz, l i b, 7.29 (d, .7-8,40 Hz, HI), 6.57 (t, ,6=6.80 Hz, IH), 4., 74 (hr. s., Hi), 4.60 (d, > 6.40 Hz, 2H>, 4.15 <q. 7 7 I , 211), 2.75 ~ 2.85 (m, IB), 2.54 (s, 311), 2,32 is, 3H), 1.85 -2.10 (m _s 4H), 1.60 - 1 75 (ffi, 4H), 1 ,2? (t J ^:: 72 Hz , 3H).

Example 1. (1 S3S>3~((6~(3-m;eihyE4 ((i5-propyl~l .S-l-tliiadlazol-S- y!)amiao) ethyl)isoxa2i>I-5-yl) acid

LA, (5 (5-bromopyridin~2-yl)A-me hyIisoxazol~4~yI)metlianoi

A solution of lM B¾.THF in TBF (14.8 raL, 14.8 mmol) was added dropwise to a solution of 5 (5-br0mopy.ddIn-2--yl) -3-meibyliso>:.azolc-4-carboxyiic acid (1.67 g, 5.90 mmol) (prepared according to the procedure ofNagasue, 11. IP 201.7095. >66) in TL!F (25 mL). 1¾e reaction was stirred at 60 °C for 2 h, then wan cooled to 0 °C and cautiously quenched with HOAe (1 mL) and MeQH (10 mL) at 0 °C, The mixture was allowed to warm to l¾J and MU S cd at R ^' T for 30 min. then was concentrated in. vacuo. FvleOH (30 ml) was added and the nu.vmre was stirred for 30 min. at .RT, then was concentrated in vacuo. The residue was diluted with said aq. NaB€C¾ (15 L) and extracted with EtQAc (5 x 20 mL), The combined organic extracts were washed with brine, dried (MgSCA) and concentrated In vacuo. The crude product was chromatographed (40 g SiOs. continuous gradient from 0 to 100 % EtOAc over 15 min) to afford the title compound (.1 ,20 g, 4.46 mmol, 76 % yield) as a white solid. ¾ NMR (500 MHsr, CDCh) § 8.75 (dd, J- 2.3, 0.7 H¾ IB), 8.05 (dd, ,/·- 8,5, 2,4 ¾ 1 Id), 7.90 (dd, ,/- 8.5, 0.8 1¾ IH) 4.63 (s, 2B), 2.36 (s, 3B). [Mtfif - 269. IB. 5-(S-bronK>pyriditt-2wi) 3 -niethyI-4~(iitettahydro3!d~pyran~2 · yl}oxy)meChyI)isoxaxote

r-T$0M I¾0 (18 mg, 0.096 mmol) was added to a 0 °C solution of 1A (516 mg _»

L918 mmol) and 3,4~dihydro~2H-pyi¾u (0.53 uiL, 5.75 mmol) m DCM (6 ml.} Th.e reaction was stirred for 48 ii at Rd ^' , then was cooled to ø M and neutralized with satd aq. NaHCOs to pH ~ ? TM mixture was partitioned between DCM (10 mL) am! water (10 ml,); the aqueous layer was extracted with DCM((3 x 10 ml), The combined organic extracts were dried (MgSCq) and concentrated in vacuo. The residue was

chromatographed (40 g SiCb, continuous gradient from 0 to 50% BtQAc/hexanes over 15 min) to afford the title compound (640 mg, 1. 12 mmol 94 % yield) as a colorless oil. ¾ NMR (500 » _s CDCR) d 8 74 (dd, _< /- 2.4, 0.8 I¾ i l l), 7.93 (dd, J - 8.5, 23 I lx. IH)

4

A mixture of Pdeidbals (100 nig, 0.109 mmol) di-tert-butylC yd’^ -triisopropyl

[Lr-biphe»yI] 2~y!)phospIiine (185 mg, 0,435 mmol), KOH (610 mg, 10.87 mmol) and IB (640 mg, 1..81 mmol) in -dioxane (5 xnL) and water (5 mL) was quickly evacuated and backfilled with Ar (repeated 3X), The mixture was stirred at 8533 for 14 k then was cooled to I¾-T and carefully acidified with aq IN HClto pH 4. BtOH (2 mL) was added and the mixture was extracted with EtOAc: (8 x 5 mL). The co bined organic extracts were dried (MgSCB) and concentrated in vacuo The crude residue was chromatographed (40 g SiQ¾ continuous gradient from 0 to 100% EtOAc in hexanes over 14 min) to afford the title compound (275, mg, 0.947 mmol, 52.3 % yield) as a slightly colored oil ¾ NMR (500 Ml¾ CDCis) 6 8.33 (d, ,/ - 2.8 Hz, I II), 7.72 (d, 7 8,6 Hz, IHh 7 26 (dd _* /- 8 6. 2 8 Hz, 1H), 5.02 (d, J~ 1 1.9 Hz, !H), 4.91 (d, /* 12.0 Hz, 1H), 4.7? (dd, 7 - 4.5, 2.9 Hz. 1H), 3.94 (ddd. 7- 1 1 ,5, 8.0, 3.2 Bx, IT!), 3.55 (did, - 10,7, 4 7, 4.2, 2.3 ¾ 1 H), 2.40 (s, 3H), L86 - 1 45 (m. 60). jjVETij - 291 d .

ID. Isopropyl (1 S,3S)7v-((6-(3-methyi~4-(((teitahydro-2H~pyram2- yl)ox 2auethytjisoxazoLSyd)pyridir-l3wi)oxy)eycloIiexane-Eearboxyl ate

To a 0 ^a C mixture of 1C (275 mg, 0.947 mmol), (I S,3R)"isopropyi 3~

hydroxycyelo-foexaneearboxylate (318 mg, 1.71. mmol), BtsN (0.238 mL, 1 ,71 mmol) and R1¾ (447 rng, 1.71 mmol) in THF (4 mL) was added DIAD (0.33 mL, 1.71 mmol) dropwise over 5 min. The reaction was stirred at RT for 5 days, then was diluted with ¾0 (3 mL) and extracted with EtOAc (3x5 mL). The combined organic extracts were dried {MgSC } and concentrated in vacuo. The crude product was chromatographed (40 g SiOy continuous gradient from 0 to 60% BiOAe/hexanes over 20 min) to afford the title compound (21? mg, 0.47 ai oL 50 % yield) as a slightly colore oil Ή NMR (500 MHz _* CD€¾) 5 8.3? id, 7 - 2.9 Hz, 1H) _S 7.82 (d, / ^« 8.8 ¾ 11 , 7.31 (dd, 7 8.8, 3.0

¾ 1 B), 5 08 - 4.97 ( , 20), 4.96. 4 90 (m, IK), 4,77 ... 4.66 (m, 2H), 3.93 (ddd,

11.7, 8,4, 3.2 Hz _> I.H) _S 3.57 - 3.46 (tip 1 i-1 }, 2.80 lit, J - 8. ?, 4.4 Hz, 1H), 2.40 (s* 4H), 2 03 ··· 1.48 (ro, 14H) _S 1 25 6,2, 2.4 Hz, 6H) [M-H - 459.3.

1 E. Isopropyl (lS.3S}-37(6~(4~{hydraxwmediyl)-3-methy!isoxazoIv5~yi)pyrida i-3-yl)0xy) cy ohexane - i -ear boxy 1 ate

To a solution of ID (175 g. 0.38 ni ol) in MeOH (3 niL) was added PI S (9.6 mg, 0.038 mmol), The mixture was heated at 60 ^¾ C for 2 h _? the was cooled to I¾T, quenched with sat'd aq NaHGOf (2 ml..) and concentrated in vacuo to remove the eOH The residue was extracted with EtOAc \ 3 x 5 nil), The combined organic extracts were dried (MgSCL) end concentrated in vacuo. The crude product was chromatographed (12 g SiO _¾ continnous gradient from 0% to 100% EtOAc thcxanes over 11 mm) to afford the title compound (75 mg, 53 % yield) as a white solid ¾ NMR (500 ¾ CDCb) § 8.35 (d, ./- 2.9 B¾ IH), 7 93 (d, ,/- S 7 Hz, 1 B) 7.44 (dd, / - 8.8, 2.9 Hz, 1H), 6.14 (t ,7- 6 8 Hz, IH), 5.0 (hept, 6,2 Hz, ill), 4.74 (sip, J- 5.8, 2.8 Hz. 1H), 4,60 id, _· / - 6,7 Hz, 2H), 2,80 (it, ,/ 8 7, 4,2 Hz, 1 B), 2.34 (s, 3H), 2 08 - 1 55 (ni, BIT), 1.22 (d, 2 - 6. Hz, 6B) -Hf - 375.2

I F, isopropyl (lS,3S)foT(6T4Tbromomefeyi)0-raethyiisoxa2:o! 5~yI)pyridin-3~ yl}oxy)eyclO hex;nuo j -carboxylate

PBn (0.16 mL, 1.67 mmol) was added to a solution of IE (208 mg, 0 556 mmol) in DME (4 ml. ; at 0 °C . The reaction was stirred for 1 h at 1-07 theft was cooled to 0 °C and neutralise with said aq, MaHCOs to pH 7 The mixture was partitioned between DClvl (: mL) and H;0 (7 ml); the aqueous layer was extracted with C¾Cb (3 5 mL). The combined organic extracts were dried (M gSO) and concentrated in vacuo. The crude product was cbrcsmatographed (12 g SiOj; continuous gradient from 0% to 60% EtOAe: Hexanes over 1 1 ml»} to afford the title compound (198 mg. 0.45 mmol, 80 % yield) as a white solid, ¾ NMR (500 MHz, Cl») § 8.43 (4, J- 2,9 ¾ HI), 7.86 (4 - 8.8 Hz, IB) 7 36 (d& _f J =- 8.8, 2 9 Hz, i ll), 5 06 (dq, 7 12.5. 6.5 Hz, lit), Sill (s,

20), 4.76 (qd, ,/~ 5.5, 4 8, 2.5 Hz, 10), 2 82 (did, J ------ 8.S, 6.5, 4 1 F¾ 10), 2 42 (s, 3B),

5 2 0? 1.57 (m, 8H), 1,27 (del J ----- 6.3, 2.9 Hz, 60). [hB-H] - 438,0,

Example 1

To a solution of 5~pn>pyffl ₅ 3 _; 4-ihiadiazol 2 am.me (7 mg, 0.046 mmol) m THF (0 5 mb) was added Nall (3 g of a 60% sus ensi n m oil 0.03 mmol). The reaction 0 mixture was stirred at R.T for 10 min, after which llf (10 mg, 0,023 mmol) in THF (0,2 it) wa added. The reaction mixture te s s irred at RT tor 4 h, after which TvleOH (0.5 m) ) ar.d aq LiDRXbO (19 mg, 0.46 mmol) in ffcO (0.5 ml,) was added. The reaction as stirred at RT for 14 h, then was concentrated vacuo: . The residue was taken up in EtOAe (2 mL)il¾0 (ImL), and the solution was adjusted to pH -· 4-5 with I aq. HCL:5 The mixture was extracted with EtOAe (3 x 2 ml,); the combined organic extracts were dried (MgSC ?},axid concentrate in vacuo. The residue was dissolved in DMF an purified via preparative L C/MS: Column: XBridge Cl 8, 19 200 mm, 5-gm particles; Mobile Phase A: 5:95 MeCN:¾0 with 10 mM NikOAe; Mobile Phase B: 95:5

MeCN:¾C) with 10 mM NlftOAc; Gradient: 15-55% B over 19 mm, then. a 5-min bold0 at 1 0% B; Flow; 20 mL/mia. Fractions containing the desired product were combined and dried via centrifugal evaporation. The product was further purified via preparati ve LC/MS: Column: XBridge CI S, 19 x 200 , 5-nm particles; Mobile Phase A: 5:95 MeChkFfeO with 10 mM NlffOAe; Mobile Phase B: 95:5 MeCN;¾C) with 10 mM Kl¾OAc; Gradient: 0-60 B over 19 min, then a S-min bold at 100% B; Flow: 205 mL/ro Fractions containing the desired product were combined and dried via

centrifugal evaporation. The product was further purified via preparative LC/MS:

Column: XBridge€18, 19 200 m , 5-nm particles; Mobile Phase A: 5:95 MeCNdLO with 0 1% TFA; Mobile Phase B: 95:5 MeCN:i½0 with 0.1% IF A; Gradient: 13-53% B over 25 min, then a S- in hold at 100% B: Flow: 20 mL/min. Fractions containing the0 desired product were combined and dried via centrifugal evaporation to give the title compound (2 nig, 15% yield). Its estimated purity by LCMS analysis was 93%, LCMS, [M 4 Hf ^::: 458.2 ¾ NMR (500 MHz, DMSO-%) § 8.46 (d, J ----- 2.9 Fix, 1 B), 7.86 (d, ^» 8.8 Hz, 1H), 7-60 dd _; ^, / ^ S.S .9 ¾ l M), 4,84 (8, IB/g 4.68 (d, ,/- 48 H/,GHc 775 ti,

,/- 74 i¾ 2B), tm-Z (m, 10), 2.33 (s 3H), 201 ~ 1,46 (nx 10H) _> 0.90 (l, - 7

Hy 3H) 1 PA1 IC# - 2467 nM

Example 2 (1 S.3S)”3-((2-meib _: yl~6-(3-m.ethyl-4-(((2-ph¾iy!-2H-l ,2 ~ίph ^c oE4~

id

A ralxltue o (E)-di8ze»e~l,2diyl.bis|>iperid.ia"l-ylmetham e} (126 g, 5.0 mmol) am! Bo (125 ml.,, 5. mmol) in 1, 4 dioxane (20 ml,) was stirred at RT for 30 min in a pressure vial, intermediate 2F (760 mg.2.49? mmol) and isopropyl (lS3R)-3- hydroxycyclo-liexane-!-carboxylaie (83? mg, 449 mmol) were then added. The reaction mixture was heated t 85 C for 9 (at this point LCdvlS Indicated die formation of the desired product). The reaction was cooled to RT, diluted with DCM, filtered and concentrated in vacuo. The crude product was chromatographed (80 g SiOx cmumu-.ms gradient from 0% to 50% litOAc in Hexane over 25 min, hold at 50% BtOAc for 20 min) to give the title compound (618 mg, 1.31. mmol, 524 % yield) as a light yellow oil [MX Hf- 4731. 2B isopropyl ( 1 $ _s 3$}-3 -((6-(4 <l}ydroxytnethyl)3~methylispxa¾oi~5-yl>2-tnethyipyrEd in~ S-yTioxyicyclohexane-l-carhoxylate

To a solution of 2A (61.8 mg, 131 mmol) In Mol >1 1 3 niL) was added PFTS (49 mg, 0,20 mmol) The reaction was heate at.60 ^¾ C for i b, then was cooled to IT and eoneenitaied in vacuo. The mixture was partitioned between said aq, NaHO¾ and BtOAe, The aqueous layer was extracted with BtOAe (3X) The combined organic extracts were washed with water and brine, dried (MgSCh) and concentrated in vacuo. The crude oil was chromatographed (40 g SiCh; continuous gradient from 0%- 100% BtOAe hexane over 15 min) to give the title compound (460 mg _s 1.18 mmol 91 yield) as a clear oil [M T H =? 389.2.

2C. Isopropyl (18 8)-3-((6^4-To«h> ^, :ΐ3 ·hioίIigI1§qC8ZqI-5-g )-2-hk ^g 1r>·hϋIo-3->Ίΐ c>') cyclohexane- i-earhoxy!ale

To a 0°C solutio of 2C (0.110 g, 0.28 rtintol) in€¾.€¾ (2.5 ml,) were added NaHCCh (0.119 g, 1.42 mmol) and Dess-Martin periodinane (0,144 g, 0 34 mmol) and the reaction was stirred at ET for 1 h. TLC (hexanes/BiOAc ^:::: 1 /3) showed the disappearance of starting material and appearance of the product. The white solid was filtered off through Celite and the solids were rinsed with EtOAe, The combined filtrates were washed with satd aq. Nal-ICD.n water and brine, then dried (NaaSCrt) and

too concentrated m vacuo. The crude product was chromatographed (12 g SiO¾ continuous gradient from O%~20¾ BiOAc in hesasCS over 20 min) to give the title compound (100 mg, 0.26 rnmnl 91 % yield) as a colorless oil.

[M t H|" - 387.2

Example 2

T a RT solution of 2C (15 rug, 0.039 aimol), 2~phenyh2H-I _s 2 -tnazol"4-a¾ninc (9.33 mg, 0 038 mniol) inDCM (0.5 ®L) was added Ti(OJPf) _3: Cl (0.021 mL, 0107S mmol) The reaction was stirre for 2 h at RT, then NaBHiOAcn (17 mg, 0.078 ol) and TFA (0 018 ml,, 0.233 mmol) were added. The reaction mixture was stirred at RT for 18 h, after which said aq, NaHCTF was added. The aqueous layer was extracted with EiOAc (3X), The combined organic extracts were washed with brine, drie (MgSCX) and concentrated in vacuo. The: erode residue was chromatographed (4 g Si02; continuous: gradient from 0% to 100% EiC e in Hexane over 10 mm) to give the isoxaaole-irianole eyiohexyl ester as a dear oil Thi cyclohexyl ester was stirre with 1 0 M aq. aOH (0 542 niL, 0.54 mmol) in THF (1 tnLj/MeQI l (0.2 ml,) at RT for 18 h, then was concentrated in vacuo, The crude product was purified by preparative _: LC/M5

(Column; XBrklge CIS, 19 200 mm, S-prn particles; Mobile Phase A: 5:95 Me€ ;Hi(> with 0.1% TEA; Mobile Phase B; 95:5 MeCN:i¾0 with 0.1% TFA; Gradient; 36-76% B over 20 in then a 4~min hold at 100% B; Flow; 20 mL/min.) to gi ve the title compound (TFA salt; 21 mg, 0.029 mmol, 74.7 % yield) as a light yellowish oil ^l H NMR (500 Ml¾ DMSO-ds) d 7 75 - 7.68 (m, 3H), 7.56 (d _: , >8.9 H¾ I B), 7.44 (t, >7.9 Hz, 2B), 7.38 (s, 1H), 7.2 - 7.22 (m, IH), 4.86 (br s, B-l), 4,62 (s, 2H), 2.64 (hr t, 10.4 Hz, ill), 2 47 (s, 3H), 2 38 (s, 3H), 2,09 - 2.00 (m, 1 B), 1.94 · 1.78 (m, 3H), 1.71 - 1 -48 (m, 4B): MS (ESI) m/z; 489 1 (M÷Hf

The Examples in Table 1 below were synthesized according to the procedures described for the preparation of Examples 1 and 2, Table: 1

Other features of the invention should become apparent m the course of the above descriptions of exemplary embodiments that are given for illustration of the invention and are not intended fo be limiting thereof ^' Die present invention may he embodied in other specific forms without departing from the spirit or essential attributes thereof This invention encompasses all combinations of preferred aspects of the invention noted herein. It is understood tha any and ail embodiments of the present inven ion may be taken in. conjunction with any other embodiment or embodiments to describe additional embodiments. It is also understood that each individual element of the embodiments is its own independent embodiment Furthermore, any element of an embodiment Is meant to be combined with any and all other elements fro any embodiment to describe an additional embodiment