Selective heterocyclic compounds sphingosine 1 phosphate receptor modulators, their use and pharmaceutical composition

Abstract

Compounds that selectively modulate the sphingosine 1 phosphate receptor are provided including compounds which modulate subtype 1 of the SlP receptor. Methods of chiral synthesis of such compounds is provided. Uses, methods of treatment or prevention and methods of preparing inventive compositions including inventive compounds are provided in connection with the treatment or prevention of diseases, malconditions, and disorders for which modulation of the sphingosine 1 phosphate receptor is medically indicated.

Description

[0001] This application claims priority over patent applications with serial numbers US 61 / 261,295, filed November 13, 2009, and US 61 / 262,474, filed November 18, 2009, the descriptions of which are incorporated herein in their entirety. FIELD OF THE INVENTION

[0002] The present invention relates to compounds that are agonists of the sphingosine 1-phosphate receptor subtype 1, methods of their synthesis and methods of their therapeutic and / or prophylactic use. BACKGROUND

[0003] The SIPi / EDGi receptor is a G protein-coupled receptor (GPCR) and is a member of the endothelial cell differentiation gene (EDG) receptor family. Endogenous ligands for EDG receptors include lysophospholipids such as sphingosine 1-phosphate (S1P). Like all GPCRs, receptor binding propagates second messenger signals through the activation of G proteins (alpha, beta, and gamma).

[0004] The development of small molecular S1Pi agonists and antagonists has provided insight into some physiological roles of the S1Pi / S1P receptor signaling system. S1Pi receptor agonism disrupts lymphocyte trafficking, sequestering them in lymph nodes and other secondary lymphoid tissue. This leads to rapid and reversible lymphopenia, and likely occurs due to Petition 870210054926, dated 06 / 18 / 2021, p. 6 / 238 2 / 198 receptor binding occurs on both lymphatic endothelial cells and lymphocytes themselves (Rosen et al., Immunol. Rev., 195:160-177, 2003). A clinically valuable consequence of lymphocyte sequestration is their exclusion from sites of inflammation and / or autoimmune reactivity in peripheral tissues.

[0005] S1Pi agonism has also been reported to promote the survival of oligodendrocyte progenitors (Miron et al., Ann. Neurol., 63:61-71, 2008). This activity, together with lymphocyte sequestration, would be useful in treating inflammatory and autoimmune conditions of the central nervous system. SUMMARY OF THE INVENTION

[0006] The present invention relates to heterocyclic compounds adapted to act as agonists of the S1P receptor subtype 1, S1Pi; methods of preparation and methods of use, such as in the treatment of a disease mediated by S1Pi activation, or when S1Pi activation is medically indicated.

[0007] Certain embodiments of the present invention comprise a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, homologue, tautomer, stereoisomer, or hydrate or solvate thereof: (I).

[0008] A dashed line means that a single bond or a double bond may be present, provided there are two double bonds and three single bonds in the ring comprising A1, A2, and A3. A1, A2, and A3 may each independently be C or S or N; provided that one of A1, A2, and A3 is S. Petition 870210054926, dated 06 / 18 / 2021, p. 7 / 238 3 / 198

[0009] R1 can be disubstituted phenyl or disubstituted pyridyl where the phenyl and pyridinyl substituents can independently be any one of halo, nitro, cyano, perfluoromethyl, fluorinated methyl, -COOH, -COOR3, and C1-4-alkoxy. When R1 is disubstituted phenyl, such phenyl is para-substituted by C1-4-alkoxy. R2 can be where a wavy line indicates a connection point. X can be -NR'R or -OR';

[00010] R' can be H, C1-4 alkyl, n-hydroxy C1-4 alkyl, -SO2-R3, or -CO-R3. R can be H, -SO2-R5, C1-4 alkyl optionally substituted by 1 or more R4, or a ring portion optionally substituted by R6 where such ring portion is piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl. R''' can be H, C1, 4 alkyl, or -CO-R3. R' and R' obtained together with the nitrogen atom to which they are attached can form a saturated heterocyclic ring with 4, 5, or 6 members containing 0 or 1 additional heteroatom where such additional heteroatom is O or N where such heterocycle is optionally single or multiple substituted by substituents independently selected from the group consisting of OH, oxo, -NH2, n-hydroxy-C1-4 alkyl, -COOH, -(CH2)m-COOH, -(CH2)mCOOR3, -N(R3R3), and -(CH2)m-CO-N(R7R7). Each R3 can independently be C1-4 alkyl or H.Each R4 can independently be H, halo, OH, oxo, =NH, NH2, -COOH, F, -NHR3, N(R7R7), -SO2-R3, -SO2-N(R7R7), -N(R3)-SO2-R3, -COOR3, -OCO-R3,. Petition 870210054926, dated 06 / 18 / 2021, page 8 / 238 4 / 198 CO-N(R7R7), -N(R3)-COR3, C1-3 alkyl, C1-3 alkoxy, and a ring portion optionally substituted by R6 wherein such ring portion is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutynyl, or phenyl. Each R5 may independently be R4, C1-4 alkyl, C3-6 cycloalkyl, or C1-4 alkyl optionally substituted by one or more R4. Each R6 can independently be halo, OH, -NH2, -NHR3, -N(R3R3), -COOH, -COOR3, -NHCO-R3. Each R7 can independently be C1-4 alkyl or H, or two R7s obtained together with the nitrogen atom to which they are attached can form a saturated heterocyclic ring with 4, 5, or 6 members containing 0 or 1 additional heteroatom where such additional heteroatom is O or N, in which such heterocycle can optionally be substituted by -OH, -NH2, -N(R3R3), n-hydroxy C1-4 alkyl, -(CH2)mCOOH, -(CH2)m-COOR3. Each m can independently be 0, 1, 2, or 3.

[00011] In certain embodiments, a pharmaceutical composition is provided comprising a compound of the invention and a suitable excipient.

[00012] In certain embodiments, a method of using an inventive compound is provided which comprises the preparation of a medicament.

[00013] In certain combinations, a pharmaceutical combination is provided comprising a compound of the invention and a second medicinal product. In several embodiments, the second medicinal product is medically indicated for the treatment of multiple sclerosis, transplant rejection, acute respiratory distress syndrome or adult respiratory distress syndrome.

[00014] In certain embodiments, a method of activating or agonizing a sphingosine-1-phosphate receptor of subtype 1 is provided, comprising placing the subtype 1 receptor in contact with Petition 870210054926, dated 06 / 18 / 2021, page 9 / 238 5 / 198 a compound according to claim 1. In various embodiments, the compound according to claim 1 activates or agonizes the sphingosine-1-phosphate receptor of subtype 1 to a greater degree than the compound activates or agonizes a sphingosine-1-phosphate receptor of subtype 3.

[00015] In certain modalities, a method of treating a disease is provided in a patient for whom activation or agonism of an S1Pi receptor is medically indicated. In several modalities, selective activation or agonism of an S1Pi receptor, such as with respect to a SIP3 receptor, is medically indicated. In several modalities, the disease includes multiple sclerosis, transplant rejection, or acute respiratory distress syndrome.

[00016] In certain embodiments, a method is provided for the chiral synthesis of certain compounds, including the compounds of the invention. In certain other embodiments, the invention provides certain intermediate compounds associated with such chiral synthesis methods. DETAILED DESCRIPTION OF THE INVENTION

[00017] Certain embodiments of the present invention comprise a compound having the structure of Formula (I) or a pharmaceutically acceptable salt, ester, prodrug, homologue, tautomer, stereoisomer, or hydrate or solvate thereof: (I).

[00018] A dashed line means that a single bond or a double bond may be present, provided that there are two double bonds and three single bonds in the ring comprising A1, A2, and A3. A1, A2, and A3 may each independently be C or S or N; provided that Petition 870210054926, dated 06 / 18 / 2021, p. 10 / 238 6 / 198 one between A1, A2, and A3be S.

[00019] R1 can be disubstituted phenyl or disubstituted pyridyl where the phenyl and pyridinyl substituents can independently be any one of halo, nitro, cyano, perfluoromethyl, fluorinated methyl, -COOH, -COOR3, and C1-4-alkoxy. When R1 is disubstituted phenyl, such phenyl is para-substituted by C1-4-alkoxy. R2 can be where a wavy line indicates a connection point. X can be -NR'R or -OR';

[00020] R' can be H, C1-4 alkyl, n-hydroxy C1-4 alkyl, -SO2-R3, or CO-R3. R can be H, -SO2-R5, C1-4 alkyl optionally substituted by 1 or more R4, or a ring portion optionally substituted by R6 where such ring portion is piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl. R''' can be H, C1-4 alkyl, or -CO-R3. R' and R obtained together with the nitrogen atom to which they are attached can form a saturated heterocyclic ring with 4, 5, or 6 members containing 0 or 1 additional heteroatom where such additional heteroatom is O or N where such heterocycle is optionally Petition 870210054926, dated 06 / 18 / 2021, p. 11 / 238 7 / 198 single or multiple substituted by substituents independently selected from the group consisting of -OH, oxo, -NH2, n-hydroxy-C1-4 alkyl, -COOH, -(CH2)m-COOH, -(CH2)m-COOR3, -N(R3R3), and -(CH2)m-CO-N(R7R7). Each R3 can independently be C1-4 alkyl or H. Each R4 can independently be H, halo, OH, oxo, =NH, NH2, -COOH, F, -NHR3, -N(R7R7)-SO2-R3, -SO2-N(R7R7), -N(R3)-SO2-R3, COOR3, -OCO-R3, -CO-N(R7R7), -N(R3)-COR3, C1-3 alkyl, C1-3 alkoxy, and a ring portion optionally substituted by R6 wherein such ring portion is piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutynyl, or phenyl. Each R5 can independently be R4, C1-4 alkyl, C3-6 cycloalkyl, or C1-4 alkyl optionally substituted by one or more R4. Each R6 can independently be halo, OH, -NH2, -NHR3, -N(R3R3), -COOH, -COOR3, NHCO-R3.Each R7 can independently be C1-4 alkyl or H, or two R7s obtained together with the nitrogen atom to which they are attached can form a saturated heterocyclic ring with 4, 5, or 6 members containing 0 or 1 additional heteroatom where such additional heteroatom is O or N in which such heterocycle can optionally be substituted by -OH, -NH2, -N(R3R3), n-hydroxy C1-4 alkyl, -(CH2)m-COOH, -(CH2)m-COOR3. Each m can independently be 0, 1, 2, or 3.

[00021] In certain embodiments, the compounds of the invention have the structure of a specific Formula I compound or a pharmaceutically acceptable salt, ester, prodrug, homologue, hydrate, or solvate thereof. In certain embodiments, the invention provides compounds that are substantially enantiomerically pure. In certain embodiments, the compounds are enantiomerically pure with respect to a chiral carbon in an indanyl or tetrahydronaphthalenyl moiety.

[00022] In certain embodiments, the invention provides compounds having an EC50 as a receptor agonist of Petition 870210054926, dated 06 / 18 / 2021, p. 12 / 238 8 / 198 S1P of wild-type subtype 1 that is at least ten times smaller than the EC50 of such a compound as an agonist of a mutant S1P subtype 1 receptor that has a single mutation relative to the wild-type S1P subtype 1 receptor such that the 101st amino acid residue is changed from asparagine to alanine.

[00023] In certain embodiments, the invention provides compounds having an EC50 as an agonist of the wild-type S1P receptor that is at least twenty times lower than the EC50 of that compound as an agonist of a mutant S1P receptor having a single mutation with respect to the wild-type S1P receptor such that the 101st amino acid residue is changed from asparagine to alanine.

[00024] In certain embodiments, the invention provides compounds having a therapeutic index of at least 5 as measured in rats over 5 to 14 days of dosing in rats with the compound, where the therapeutic index is calculated as a ratio between (i) the highest dose of such compound that achieves a less than or equal to ten percent increase in the lung-to-body weight ratio at the conclusion of those 5 or 14 days of dosing, and (ii) the dose of that compound that achieves 50% lymphopenia in rats. In certain embodiments, this therapeutic index is at least 10, and in certain embodiments, the therapeutic index is at least 20. In certain embodiments, the therapeutic index for a compound is at least five times greater than the therapeutic index for the enantiomer of that compound.

[00025] In certain embodiments, the invention provides compounds having a therapeutic index of at least 5 as measured in rats following 5 or 14 days of dosing in rats with the compound where the therapeutic index is calculated as a ratio between (i) the highest dose of such compound that achieves a less than or equal increase Petition 870210054926, dated 06 / 18 / 2021, page 13 / 238 9 / 198 to ten percent in the ratio of lung to terminal body weight at the conclusion of these 5 or 14 days of dosing, and (ii) the dose of this compound that achieves 50% lymphopenia in rats. In certain embodiments, this therapeutic index is at least 10, and in certain embodiments, the therapeutic index is at least 20. In certain embodiments, the therapeutic index for a compound is greater than the therapeutic index for the enantiomer of that compound. In certain embodiments, the therapeutic index for a compound is at least 150% of the therapeutic index for the enantiomer of that compound.

[00026] In certain embodiments, the invention provides compounds where the structure of Formula I is selected from the group consisting of Formulas ai to ax:

[00027] In certain embodiments, the invention provides compounds where A1 is S; in other embodiments, the invention provides compounds where A2 is S; and in other embodiments, the invention provides compounds where A3 is S. In certain embodiments, A1 is N and A2 is C or N; in certain embodiments, A2 is Petition 870210054926, dated 06 / 18 / 2021, page 14 / 238 10 / 198 C and in others A2 is N.

[00028] In certain embodiments, the invention provides compounds where R1 is O--\ / -R3I / / Y;

[00029] Each R3 is independently C1-4 alkyl; and Y is -CN, -Cl, I, -O-R3, -COOH, -COOR3, or -CF3. In certain embodiments R3 is isopropyl or ethyl. In certain embodiments Y is -CN or -O-C2H5. In certain embodiments Y is -COOR3.

[00030] In certain embodiments, the invention provides compounds where R2 is

[00031] In certain embodiments, the invention provides compounds where R2 is Petition 870210054926, dated 06 / 18 / 2021, p. 15 / 238 11 / 198 or

[00032] In other embodiments, the invention provides compounds where R2 is

[00033] In certain embodiments the compound is substantially enantiomerically pure.

[00034] In certain embodiments, the invention provides compounds where Y is Cl, in other embodiments, the invention provides compounds where Y is CF3, and in other embodiments, the invention provides compounds where Y is CN. In certain embodiments, the Petition 870210054926, dated 06 / 18 / 2021, p. 16 / 238 12 / 198 The invention provides compounds where Y is I. In certain embodiments, the invention provides compounds where Y is -COOH. In certain embodiments, the invention provides compounds where Y is -COOR3.

[00035] In certain embodiments, the invention provides compounds where X is -NR'R, in other embodiments, the invention provides compounds where X is -OR'. In certain embodiments, the invention provides compounds where X is -OR'''. In certain embodiments, the invention provides compounds where X is -OH and in other embodiments, the invention provides compounds where X is -OCO-R3.

[00036] In certain embodiments, the invention provides compounds where R3 is C1-3 alkyl; in other embodiments, the invention provides compounds where R' is H.

[00037] In certain embodiments, the invention provides compounds where R' is -COR3; in other embodiments, the invention provides compounds where R' is SO2-R3. In certain embodiments, the invention provides compounds where R is H.

[00038] In certain embodiments, the invention provides compounds where R is -SO2-R5; in other embodiments, the invention provides compounds where R is C1-4 alkyl where C1-4 alkyl is optionally substituted by 1 or more substituents defined by R4. In certain embodiments, the invention provides compounds where R is -(CRaRb)n-R4 and each Ra and each Rb can independently be any one of H, hydroxyl and methyl or where Ra and Rb are bonded to the same carbon and can be obtained together to form oxo (i.e., with the carbon to which these are bonded forming a carbonyl moiety). In certain embodiments n can be 0, 1, 2, or 3 and in some embodiments n is 2. In certain embodiments R2 can be -OH, -NH2, -NHR3, -N(R7R7), or -COOH. Petition 870210054926, dated 06 / 18 / 2021, p. 17 / 238 13 / 198

[00039] In certain embodiments, the invention provides compounds where R5 is C1-4 alkyl optionally substituted by 1 or more R4. In certain embodiments, the invention provides compounds where R4 is OH; in other embodiments, the invention provides compounds where R4 is C1-3 alkoxy. In certain embodiments, the invention provides compounds where R5 is (CH2)2-OR3.

[00040] In certain embodiments, the invention provides compounds where Y is CN and X is -NH-SO2-R5. In certain embodiments, the invention provides compounds where R5 is -C2H5N((R7R7) or -CH2-CO-N(R7R7). In certain embodiments, the invention provides compounds where Y is CN and X is -NH-CON(R7R7).

[00041] In certain embodiments X is -NH2 and in certain embodiments Y is CN.

[00042] In certain embodiments, the invention provides one or more of the compounds 1-227: Petition 870210054926, dated 06 / 18 / 2021, p. 18 / 238 14 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 19 / 238 15 / 198 THE O n-\ Hx Petition 870210054926, dated 06 / 18 / 2021, p. 20 / 238 16 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 21 / 238 17 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 22 / 238 18 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 23 / 238 19 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 24 / 238 20 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 25 / 238 21 / 198 Petition 870210054926, dated 06 / 18 / 2021, p. 26 / 238 22 / 198 or any pharmaceutically acceptable salt, tautomer, stereoisomer, solvate, hydrate, or prodrug thereof. In certain embodiments, the invention provides a compound selected from compounds 43, 46, 47, 56, 58, 166, 172, and 186 or any pharmaceutically acceptable salt, ester, tautomer, stereoisomer, solvate, hydrate, homologue, or prodrug thereof. In certain embodiments, the invention provides compound 43, 46, or 166 or any pharmaceutically acceptable salt, ester, tautomer, solvate, hydrate, homologue, or prodrug thereof.

[00043] In certain embodiments, a compound of the invention of Formula I is provided in which the compound has at least one chiral center and is substantially enantiomerically pure.

[00044] In other embodiments, a pharmaceutical composition is provided comprising a compound of the invention of Formula I and a suitable excipient.

[00045] In other embodiments, a pharmaceutical combination is provided comprising a compound of the invention and a second medicinal product. In still other embodiments, a Petition 870210054926, dated 06 / 18 / 2021, page 27 / 238 23 / 198 pharmaceutical combination comprising a compound of the invention and a second medicinal product wherein the second medicinal product is medically indicated for the treatment of multiple sclerosis, transplant rejection, or acute respiratory distress syndrome in adults.

[00046] In certain embodiments, a method is provided for using a compound of the invention for the preparation of a medicament.

[00047] In certain embodiments, a method is provided for activating or agonizing a sphingosine-1-phosphate receptor of subtype 1 by placing the subtype 1 receptor in contact with an effective amount of a compound of the invention. In further embodiments, a method is provided for activating or agonizing a sphingosine-1-phosphate receptor of subtype 1 by contacting the subtype 1 receptor with an effective amount of a compound of the invention, wherein the compound activates or agonizes the sphingosine-1-phosphate receptor of subtype 1 to a greater extent than the compound activates or agonizes a sphingosine-1-phosphate receptor of subtype 3. In further embodiments, a method is provided for activating or agonizing a sphingosine-1-phosphate receptor of subtype 1 by contacting the subtype 1 receptor with an effective amount of a compound of the invention, wherein the sphingosine-1-phosphate receptor of subtype 1 is disposed in a live mammal.

[00048] In certain embodiments, a method is provided for treating a disease in a patient for whom medically indicated activation or agonism of a sphingosine-1-phosphate receptor of subtype 1 is provided by administering an effective amount of a compound of the invention to the patient at a frequency and over a duration of time sufficient to provide a beneficial effect to the patient. In further embodiments, a method is provided for treating a disease in a patient for whom medically indicated activation or agonism of a sphingosine-1-phosphate receptor of subtype 1 is provided by administering an effective amount of a compound of the invention to the patient at a frequency and over a duration of time sufficient to provide a beneficial effect to the patient. Petition 870210054926, dated 06 / 18 / 2021, page 28 / 238 24 / 198 medically the activation or agonism of a sphingosine-1-phosphate receptor subtype 1, by administering an effective amount of a compound of the invention to the patient at a frequency and over a duration of time sufficient to provide a beneficial effect to the patient, wherein the selective activation or agonism of an S1P receptor subtype 1 relative to other S1P receptor subtypes is medically indicated. In further embodiments, a method is provided for the treatment of a disease in a patient for whom activation or agonism of a sphingosine-1-phosphate receptor subtype 1 is medically indicated, by administering an effective amount of a compound of the invention to the patient at a frequency and over a duration of time sufficient to provide a beneficial effect to the patient, wherein the disease comprises rejection of transplanted organs or tissues; graft-versus-host disease caused by transplantation;autoimmune syndromes including rheumatoid arthritis; acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; cancer; systemic erythema; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I and II diabetes; uveitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; cutaneous manifestations of immunologically mediated disorders; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrheic dermatitis; lichen planus; pemphigus; bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis;corneal epithelial dystrophy; corneal leukoma; ocular pemphigus; ulcer; Petition 870210054926, dated 06 / 18 / 2021, page 29 / 238 Mooren's syndrome 25 / 198; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late-onset asthma and airway hyperresponsiveness; bronchitis; gastric ulcers; ischemic bowel diseases; inflammatory bowel diseases; enterocolitis; burn-related bowel injuries; celiac disease; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular injury caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; myocardial infarction; arteriosclerosis; aortitis syndrome; Cachexia due to viral diseases; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis;glomerulonephritis; multiple myositis; Guillain-Barré syndrome; Meniere's disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia; megaloblastic anemia; anerithroplasia; osteoporosis; sarcoidosis; pulmonary fibrosis; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergic sensitivity; cutaneous T-cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma; Wegener's granuloma; Sjögren's syndrome; adiposis; eosinophilic fasciitis; Gum, periodontium, alveolar bone, and dental bone lesions; androgenetic alopecia or senile alopecia; muscular dystrophy; pyoderma; Sézary syndrome; chronic adrenal insufficiency; Addison's disease;ischemia-reperfusion injury of organs that occurs through; Petition 870210054926, dated 06 / 18 / 2021, page 30 / 238 26 / 198 preservation; endotoxin shock; pseudomembranous colitis; drug- or radiation-induced colitis; acute ischemic renal failure; chronic renal failure; lung cancer; lymphoid malignancy; acute or chronic lymphocytic malignancy; leukemias; lymphoma; psoriasis; inflammatory lung injury, pulmonary emphysema; cataract; siderosis; retinitis pigmentosa; senile macular degeneration; vitreous scar; inflammatory eye disease; alkali burn on the eye; erythematous dermatitis; bullous dermatitis; cement contact dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; carcinoma metastasis; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial hepatic resection; acute hepatic necrosis; cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; late-onset hepatic failure; acute or chronic liver failure.In additional categories, the disease is one or more of the following: organ or tissue transplant rejection; graft-versus-host disease resulting from transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; psoriasis prevention; Crohn's disease; ulcerative colitis; acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; and carcinoma metastasis. In additional categories, the disease is one of the following: influenza, ulcerative colitis, multiple sclerosis, transplant rejection, acute respiratory distress syndrome, or adult respiratory distress syndrome.

[00049] In certain embodiments, methods are provided for using a compound of the invention intended for the preparation of a medicament adapted for the treatment of a disorder or disease, wherein the activation or inhibition of a sphingosine-1-phosphate receptor of subtype 1 is medically indicated. Petition 870210054926, dated 06 / 18 / 2021, page 31 / 238 27 / 198

[00050] In certain embodiments, the invention provides a method for chiral synthesis of a compound comprising an indane moiety having a chiral carbon atom in the five-membered ring of the indane moiety wherein the compound is enantiomerically enriched with respect to the chiral carbon atom. In these embodiments, the method of the invention provides the steps of (i) providing a compound comprising an indane moiety wherein the ring carbon atom of the five-membered ring of the indane moiety wherein a chiral substitution is desired is oxo substituted on such carbon atom, and wherein a carbon of the phenyl ring is halo substituted; (ii) react such compound with a chiral reagent selected from the group consisting of an oxazaborolidine of Corey Bakshita Shibata and a chiral sulfinamide of the form RS(=O)NH2 where R is selected from the group consisting of t-butyl, C2-6 branched alkyl and C3-8 cycloalkyl; and (iii) form the chiral center on the carbon of the indane moiety previously attached to the oxo group by reacting such compound with a suitable reducing agent together with the chiral reagent in step (ii) or reacting the result of the reaction of such compound with a suitable reducing agent.

[00051] In certain embodiments, R is t-butyl, sec-butyl, isopropyl, cyclopropyl, adamantyl, C3-6 branched alkyl, or optionally, C3-8 bridged cycloalkyl. In certain embodiments, the chiral reagent is Corey Bakshita Shibata's oxazaborolidine and the compound comprising an indane moiety is enantiomerically enriched with respect to a carbon-oxygen atom bond at a ring carbon atom of the five-membered ring of the indane moiety. In further embodiments, a suitable chiral reagent includes a borohydride such as BH3-DMS or NaBH4. Petition 870210054926, dated 06 / 18 / 2021, page 32 / 238 28 / 198

[00052] In additional embodiments, the chiral reagent is (R)-(-)-(2)methyl-CBS-oxazaborolidine or (S)-(-)-(2)-methyl-CBS-oxazaborolidine.

[00053] In certain embodiments the compound comprising an indane moiety provided in step (i) is brought into contact with the chiral reagent to form in step (ii) the VI-R or VI-S Formula: . (R) 'Oh COME (S) OH VI-S where Z is Cl, Br, or I.

[00054] In certain embodiments, the method further comprises the step of protecting the hydroxyl group of Formula VI-R or VI-S by treating Formula VI-R or VI-S with a protecting agent to form Formula VIa-R or VIa-S: Via-S Petition 870210054926, dated 06 / 18 / 2021, page 33 / 238 29 / 198 where PG is a protecting group.

[00055] Protecting groups can render chemical functionality inert under specific reaction conditions and can be added to and removed from such functionality in a molecule without substantially impairing the rest of the molecule. Those skilled in the art might be familiar with suitable protecting groups for use in the synthetic methods of the invention. See, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 2nd ed., John Wiley & Sons, New York, 1991. In certain embodiments, such a protecting agent is t-butyldimethylsilyl chloride (TBSCl).

[00056] In certain embodiments, the method further comprises the step of reacting Formula VIa-R or VIa-S with boronic acid or bis(pinacolate)diboron to form a boronic acid or boronate ester of Formula VIb-R or VIb-S: OPG VIb-R THE O'Bn \—os) o-pg VIb-S.

[00057] In certain embodiments the chiral reagent is RS(=O)NH2 and the compound comprising an indane moiety is enantiomerically enriched with respect to a carbon-nitrogen bond at a ring carbon of the five-membered ring of the indane moiety. In further embodiments the chiral reagent is t-BuS(=O)NH2.

[00058] In certain embodiments the compound comprising Petition 870210054926, dated 06 / 18 / 2021, p. 34 / 238 30 / 198 a portion of indane supplied in step (i) is brought into contact with the chiral reagent to form in step (ii) Formula VII-R or VII-S: Z χ,^Χ JjXN o=sv Λ VII -R Z^ / ςχ TjXN O=S. VII-S where Z is Cl, Br, or I.

[00059] In certain forms the compound of Formula VIIIR or VIII-S is formed in step (iii): Z^^x Tj \----Ir(R) 'NH VIII-R Z^^X Ij \—((S) NH O< VIII-S.

[00060] In certain embodiments the method further comprises the step of contacting Formula VIII-R or VIII-S with 1,4-dioxane in the presence of an acid to form Formula VIbR or VIb-S or Formula IX-R or IX-S: Petition 870210054926, dated 06 / 18 / 2021, p. 35 / 238 31 / 198 IX -R

[00061] In certain embodiments, the method further comprises the step of protecting the amino group by treating Formula IX-R or IX-S with a protective agent to form Formula IXa-R or IXa-S: IXa-R IXa -S.

[00062] In certain forms the protective agent is di-tert-butyldicarbonate.

[00063] In certain embodiments the method further comprises the step of reacting Formula IXa-R or IXa-S with boronic acid or bis(pinacolate)diboron to form a boronic acid or boronate ester of Formula IXb-R or IXb-S: Petition 870210054926, dated 06 / 18 / 2021, p. 36 / 238 32 / 198 TO THE O'B IXb -R THE B N-PG H IXb -S.

[00064] In certain embodiments the method further comprises the step of reacting Formula VIb-R, Formula VIb-S, Formula IXb-R or Formula IXb-S with Formula XI: Br XI to form Formula XII-R or XII-S: X-PG XII-S where each A1 and each A2 is independently N, or CH; R1 is phenyl Petition 870210054926, dated 06 / 18 / 2021, p. 37 / 238 33 / 198 disubstituted or pyridinyl disubstituted where the phenyl and pyridinyl substituents are selected independently from the group consisting of halo, nitro, cyano, perfluoromethyl, fluorinated methyl, and C1-4-alkoxy; provided that if R1 is disubstituted phenyl, such phenyl is parasubstituted by C1-4-alkoxy; and X is NH or O.

[00065] In additional embodiments R1 is disubstituted phenyl where the phenyl substituents are F and Y, where Y is -CN, -Cl, or -CF3. In further embodiments Y is -CN.

[00066] In certain embodiments the method further comprises the step of reacting Formula XII-R or XII-S with i PrOH in the presence of NaO i Pr to form Formula XIII-R or XIII-S: XPGXIII-S.

[00067] In certain embodiments, the method further comprises the step of deprotecting the hydroxyl group where X is O, or the amino group where X is NH, by treating Formula XIII-R or XIII-S with a deprotecting agent. In further embodiments, the method further comprises the step of converting the deprotected amino group into a secondary amine.

[00068] In certain modes A1 is N and A2 is N. In certain modes Formula XI is prepared after the process Petition 870210054926, dated 06 / 18 / 2021, p. 38 / 238 34 / 198 which includes the stage of (a) treat a disubstituted benzaldehyde with monobasic potassium phosphate to form a disubstituted benzoic acid; b) bring the disubstituted benzoic acid into contact with H2NNHCSNH2 to form an amino-1,3-4-thiadiazole having a disubstituted phenyl group in the thiadiazole portion; and c) treat the amino-1,3-4-thiazisol in step b) with a mixture of copper bromide and isoamyl nitrite.

[00069] In certain modalities, A1 is N and A2 is CH. In certain modalities, Formula XI is prepared after the process that includes the step of a) bring 2-bromothiazole into contact with a (disubstituted phenyl)boronic acid to form a 2-(disubstituted phenyl)thiazole; and b) treat 2-(phenyl disubstituted)thiazole with NBS.

[00070] In certain modalities, A1 is CH and A2 is N. In certain modalities, Formula XI is prepared after the process that includes the step of a) bring 5-(tributylstanyl)thiazole into contact with an iodobenzene that has two other substituents to form a 5-(disubstituted phenyl)thiazole; and b) treat 2-(phenyl disubstituted)thiazole with NBS.

[00071] In certain embodiments, the method of the invention provides the steps of (i) providing the compound (ii) reacting such a compound with a chiral reagent is an oxazaborolidine of Corey Bakshita Shibata and X is -OR'. In Petition 870210054926, dated 06 / 18 / 2021, page 39 / 238 35 / 198 additional embodiments, the chiral reagent is (R)-(-)-(2)-methyl-CBS-oxazaborolidine or (S)-(-)-(2)-methyl-CBS-oxazaborolidine.

[00072] In certain embodiments, the chiral reagent is RS(=O)NH2 where R is branched alkyl or cycloalkyl and X is -NR' R. In additional embodiments, the chiral reagent is t-Bu-S(=O)NH2.

[00073] In certain embodiments, a suitable reducing reagent includes a borohydride, such as BH3-DMS or NaBH4.

[00074] Additional steps for the preparation of such compounds may be adapted from the synthetic methods described herein, including recrystallization and other purification processes.

[00075] In certain embodiments, the invention provides a method of synthesizing a chiral compound of the invention (i) by providing a compound comprising an indane moiety wherein the ring carbon atom of the five-membered ring of the indane moiety wherein a chiral substitution is desired is oxo substituted at such carbon atom; (ii) by reacting such compound with a chiral reagent selected from the group consisting of an oxazaborolidine of Corey Bakshita Shibata and a chiral sulfinamide of the form RS(=O)NH2 wherein R is a bulky group [e.g., t-butyl or other branched alkyl or cycloalkyl]; and (iii) by forming a chiral center at the carbon atom of the indane moiety previously bonded to the oxo group by reacting such compound with a suitable reducing agent along with the chiral reagent in step (ii) or by reacting the result of the reaction of such compound with a suitable reducing agent.

[00076] Additional steps for the preparation of such compounds may be adapted from the synthetic methods described herein, including recrystallization and other purification processes.

[00077] In certain embodiments, the invention provides a method of synthesizing a chiral compound of the invention by (i) providing Petition 870210054926, dated 06 / 18 / 2021, page 40 / 238 36 / 198 a compound comprising an indane moiety wherein the ring carbon atom of the five-membered ring of the indane moiety wherein a chiral substitution is desired is oxo substituted on such carbon atom; and (ii) reacting such compound with a chiral reagent selected from the group consisting of an oxazaborolidine of Corey Bakshita Shibata and a chiral sulfinamide of the form RS(=O)NH2 wherein R is a bulky group [e.g., t-butyl or other branched alkyl or cycloalkyl]; and (iii) forming a chiral center on the carbon atom of the indane moiety previously bonded to the oxo group by reacting such compound with a suitable reducing agent together with the chiral reagent in step (ii) or by reacting the result of the reaction of such compound with a suitable reducing agent.

[00078] In certain embodiments, the invention provides a method for chiral synthesis of a chiral compound comprising an indane moiety having a chiral carbon atom in the five-membered ring of the indane moiety or a chiral compound comprising an oxadiazol-indane moiety having a chiral carbon atom in the five-membered ring of the indane moiety wherein the chiral compound has an enantiomeric enrichment of at least 75%, 85%, 90%, 95%, 98%, or 99%.

[00079] In certain embodiments, the invention provides a method for the synthesis of a chiral compound of the invention having an enantiomeric enrichment of at least 75%, 85%, 90%, 95%, 98%, or 99%.

[00080] In certain embodiments, a method is provided for the synthesis of a compound comprising an indane moiety having a chiral carbon atom in the five-membered ring of the indane moiety where the compound is enantiomerically enriched with respect to the chiral carbon atom. In certain embodiments, a method is provided comprising a step of providing Petition 870210054926, dated 06 / 18 / 2021, p. 41 / 238 37 / 198 a compound of the structures described here.

[00081] As used in the descriptive report and the attached claims, the singular forms a, an, oea include plural referents except where the context clearly indicates otherwise.

[00082] As used here, individual (in relation to the individual being treated) means both mammals and non-mammals. Mammals include, for example, humans; non-human primates, for example, baboons and monkeys; cattle; horses; sheep; and goats. Non-mammals include, for example, fish and birds.

[00083] The term S1Pi as used here refers to subtype 1 of a sphingosine-1-phosphate receptor, while the other subtype sphingosine-1-phosphate receptors are referred to accordingly, for example, the subtype 3 sphingosine-1-phosphate receptor is referred to as S1P3.

[00084] A receptor, as well known in the art, consists of a biomolecular entity that generally comprises a protein that specifically binds a structural class of ligands or a single native ligand in a living organism, this binding causing the receptor to transduce the binding signal into another type of biological action, such as signaling a cell where a binding event has already occurred, causing the cell to alter its function in some way. An example of transduction is the receptor binding of a ligand causing alteration of the activity of a G protein in the cytoplasm of a living cell. Any molecule, whether naturally occurring or not, that binds to a receptor and activates it for signal transduction is referred to as an agonist or activator.Any molecule, whether naturally occurring or not, that binds to a receptor but does not induce signal transduction, and that can block the binding of an agonist and its signal transduction. Petition 870210054926, dated 06 / 18 / 2021, p. 42 / 238 38 / 198 consequently, is referred to as an antagonist.

[00085] Depending on the usage in question, the terms S1Pi compound or S1Pi agonist or S1Pi activator or S1Pi inhibitor or S1Pi antagonist refer to compounds that interact in some way with the S1P receptor of subtype 1. They may be agonists or activators, or they may be antagonists or inhibitors. An S1Pi compound of the invention may be selective for action on subtype 1 of the S1P receptor family; for example, a compound of the invention may act at a lower concentration on subtype 1 of the S1P receptor family than on other subtypes of the S1P receptor family; more specifically, an S1Pi compound of the invention may act selectively on subtype 1 receptors compared to its action on subtype 3, or S1P3 receptors.

[00086] In certain embodiments, the compounds of the invention are orthostatic agonists. In certain other embodiments, the compounds of the invention are allosteric agonists. Receptor agonists can be classified as orthosteric or allosteric. An orthosteric agonist binds to a site on the receptor that significantly overlaps with the binding of the natural ligand and replicates the key interactions of the natural ligand with the receptor. An orthosteric agonist will activate the receptor through a molecular mechanism similar to that of the natural ligand, will be competitive with the natural ligand, and will be competitively antagonized by pharmacological agents that are competitive antagonists to the natural ligand. An allosteric agonist binds to a site on the receptor that performs some significant interactions that do not partially or completely overlap with the natural ligand. Allosteric agonists are true agonists and non-allosteric enhancers.Consequently, they activate receptor signaling on their own and without requiring a submaximal concentration of the natural ligand. Allosteric agonists can be identified. Petition 870210054926, dated 06 / 18 / 2021, p. 43 / 238 39 / 198 when an antagonist known to be competitive for the orthosteric ligand shows non-competitive antagonism. The allosteric agonist site can also be mapped by receptor mutagenesis. The introduction of single-point mutations in receptors that retain receptor activation by allosteric agonist while decreasing or abolishing orthosteric agonist-induced signaling, or vice versa, provides formal evidence for differences in binding interactions. Orthosteric agonists can destabilize GPCR structure and conformation, while allosteric agonists can either stabilize or destabilize GPCR structure and conformation. Allosteric agonists, by virtue of their different receptor interactions, can be pharmaceutically useful because the allosteric site can confer additional opportunities for agonist potency and selectivity in a related family of subtype receptors that share a similar orthosteric ligand.Furthermore, the allosteric site may require very different physical and chemical properties of an agonist compared to the orthosteric ligand. These chemophysical properties, which include hydrophobicity, aromaticity, charge distribution, and solubility, can also provide advantages in generating agonists with variable pharmacokinetics, oral bioavailability, distribution profiles, and metabolism that facilitate the development of effective pharmaceutical substances.

[00087] Depending on the usage in question, the term substantially means completely or almost completely; for example, a composition that is substantially free of a component has no component or contains a trace amount in which any relevant functional property of the composition is not affected by the presence of the trace amount, or a compound is substantially pure if there are only insignificant traces of impurities present. Petition 870210054926, dated 06 / 18 / 2021, p. 44 / 238 40 / 198

[00088] Substantially pure enantiomerically means an enantiomeric enrichment level of one enantiomer relative to another enantiomer of at least 90%, 95%, 98%, 99%, 99.5% or 99.9%.

[00089] Treat or treatment within the meaning in this document refers to the relief of symptoms associated with a disorder or disease, or the inhibition of further progression or worsening of those symptoms, or the prevention or prophylaxis of the disease or disorder.

[00090] The term "effective amount," when used to describe the use of a compound of the invention in providing therapy to a patient suffering from a disorder or disease mediated by a sphingosine-1-phosphate receptor subtype 1, refers to the amount of a compound of the invention that is effective in binding as an agonist or as an antagonist to an S1Pi receptor in the tissues of the individual, wherein S1Pi is implicated in the disorder, such binding occurring to a degree sufficient to produce a beneficial therapeutic effect on the patient. Similarly, as used herein, an effective amount or a therapeutically effective amount of a compound of the invention refers to an amount of the compound that relieves, totally or partially, the symptoms associated with the disorder or condition, or interrupts or delays further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.In particular, a therapeutically effective amount refers to an amount that is effective, in dosages and for the time periods required, to achieve the desired therapeutic result by acting as an agonist of the sphingosine-1-phosphate receptor subtype 1 (S1Pi) activity. A therapeutically effective amount is also one in which any toxic or harmful effects of compounds of the invention are outweighed by the therapeutically beneficial effects. For example, in the context of treating a disease mediated by S1Pi activation, a... Petition 870210054926, dated 06 / 18 / 2021, page 45 / 238 41 / 198 A therapeutically effective amount of an S1Pi agonist of the invention is an amount sufficient to control the disease, mitigate disease progression, or alleviate disease symptoms. Examples of conditions that can also be treated include multiple sclerosis, transplant rejection, and adult respiratory distress syndrome.

[00091] Diseases, disorders and conditions that can be treated by the compounds of the invention include rejection of transplanted organs or tissues; graft-versus-host disease caused by transplantation; autoimmune syndromes including rheumatoid arthritis; acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; cancer; systemic erythema; Hashimoto's thyroiditis; lymphocytic thyroiditis; multiple sclerosis; myasthenia gravis; type I and II diabetes; uveitis; posterior uveitis; uveitis associated with Behcet's disease; uveomeningitis syndrome; allergic encephalomyelitis; chronic allograft vasculopathy; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; cutaneous manifestations of immunologically mediated disorders; psoriasis; atopic dermatitis; osteomyelitis; contact dermatitis; eczematous dermatitis; seborrheic dermatitis; lichen planus; pemphigus;Bullous pemphigoid; epidermolysis bullosa; urticaria; angioedema; vasculitis; erythema; cutaneous eosinophilia; acne; alopecia areata; keratoconjunctivitis; vernal conjunctivitis; keratitis; herpetic keratitis; corneal epithelial dystrophy; corneal leukoma; ocular pemphigus; Mooren's ulcer; ulcerative keratitis; scleritis; Graves' ophthalmopathy; Vogt-Koyanagi-Harada syndrome; sarcoidosis; pollen allergies; reversible obstructive airway disease; bronchial asthma; allergic asthma; intrinsic asthma; extrinsic asthma; dust asthma; chronic or inveterate asthma; late-onset asthma and airway hyperresponsiveness; bronchitis; ulcers; Petition 870210054926, dated 06 / 18 / 2021, page 46 / 238 42 / 198 gastric; ischemic bowel diseases; inflammatory bowel diseases; enterocolitis; intestinal injuries associated with burns; celiac disease; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular injury caused by ischemic diseases and thrombosis; atherosclerosis; fatty heart; myocarditis; heart attack; arteriosclerosis; aortitis syndrome; cachexia due to viral diseases; vascular thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; Goodpasture's syndrome; hemolytic-uremic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; multiple myositis; Guillain-Barré syndrome; Meniere's disease; polyneuritis; multiple neuritis; mononeuritis; radiculopathy; hyperthyroidism; Basedow's disease; Thyrotoxicosis; pure red cell aplasia; aplastic anemia; hypoplastic anemia; idiopathic thrombocytopenic purpura; autoimmune hemolytic anemia; agranulocytosis; pernicious anemia;megaloblastic anemia; aneryoplasia; osteoporosis; sarcoidosis; pulmonary fibrosis; idiopathic interstitial pneumonia; dermatomyositis; leukoderma vulgaris; ichthyosis vulgaris; photoallergic sensitivity; cutaneous T-cell lymphoma; polyarteritis nodosa; Huntington's chorea; Sydenham's chorea; myocardosis; scleroderma; Wegener's granuloma; Sjögren's syndrome; adiposis; eosinophilic fasciitis; lesions of the gingiva, periodontium, alveolar bone, dental bone substance; androgenetic alopecia or senile alopecia; muscular dystrophy; pyoderma; Sézary syndrome; chronic adrenal insufficiency; Addison's disease; organ preservation ischemia-reperfusion injury; endotoxin shock; pseudomembranous colitis; drug- or radiation-induced colitis; acute ischemic renal failure; chronic renal failure; lung cancer; malignancy of lymphoid origin; acute or chronic lymphocytic malignancy; leukemias; lymphoma; psoriasis; inflammatory lung injury, pulmonary emphysema; cataracts;Siderosis; retinitis pigmentosa; macular degeneration; Petition 870210054926, dated 06 / 18 / 2021, page 47 / 238 43 / 198 senile; vitreous scar; inflammatory eye disease; alkali burn on the eye; erythematous dermatitis; bullous dermatitis; cement contact dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; carcinogenesis; carcinoma metastasis; hypobaropathy; autoimmune hepatitis; primary biliary cirrhosis; sclerosing cholangitis; partial hepatic resection; acute hepatic necrosis; cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; late-onset hepatic failure; acute or chronic hepatic failure.The particularly preferred diseases and conditions that can be treated with the compounds of the invention comprise the group consisting of organ or tissue transplant rejection; graft-versus-host disease resulting from transplantation; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, myasthenia gravis; pollen allergies; type I diabetes; psoriasis prevention; Crohn's disease; ulcerative colitis; acute respiratory distress syndrome; adult respiratory distress syndrome; influenza; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis and carcinoma metastasis.

[00092] Furthermore, compounds of Formula IR or IS are also useful, in combination with one or more immunosuppressive agents, for the treatment of diseases, disorders and conditions associated with an activated immune system and selected from the aforementioned list. According to a preferred embodiment of the invention, said immunosuppressive agent is selected from the group comprising or consisting of cyclosporine, daclizumab, basiliximab, everolimus, tacrolimus (FK506), azathioprine, leflunomide, 15-deoxyspergualin, or other immunosuppressive drugs.

[00093] All chiral, diastereomeric, and racemic forms of a structure are intended, unless a stereochemical or isomeric form is specifically indicated. The Petition 870210054926, dated 06 / 18 / 2021, page 48 / 238 44 / 198 compounds used in the present invention may include optically enriched or resolute isomers at any or all of the asymmetric atoms, as apparent from the descriptions, to any degree of enrichment. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized so that they are substantially free of their enantiomeric or diastereomeric partners, and these are within the scope of certain embodiments of the invention.

[00094] Isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers which are referred to as enantiomers. Single enantiomers of a pure compound are optically active, that is, they are capable of rotating plane-polarized light in a plane. Single enantiomers are designated according to the Cahn-Ingold-Prelog system.Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest-ranked group is pointed away from the observer. Then, if the descending order of the other groups proceeds clockwise, the molecule is designated (R), and if the descending order of the other groups proceeds counterclockwise, the molecule is designated (S). In the examples, the Cahn-Ingold-Prelog ranking is A > B > C > D. The atom with the lowest ranking, D, is oriented away from the observer. (R)-configuration (S)-configuration

[00095] Isolated optical isomer means a compound that has been substantially purified from the optical isomer(s) of Petition 870210054926, dated 06 / 18 / 2021, p. 49 / 238 45 / 198 same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight. Rotational isomerism

[00096] It is understood that due to the chemical properties (i.e., the resonance imparting some double-bond nature to the CN bond) of restricted rotation around the amide bond (as illustrated below), it is possible to observe a separate rotamer species and, even under some circumstances, isolate such species, as shown in the example below. It is further understood that certain structural elements, including steric effects or substituents on the amide nitrogen atom, can increase the stability of a rotamer to the point where a compound can be isolated, and are present indefinitely as a single stable rotamer. Therefore, the present invention includes any possible stable rotamers of compounds of the invention that are biologically active in the treatment of a disease, disorder or condition for which a compound of the invention may be effective as described herein. Regioisomerism

[00097] The preferred compounds of the present invention have a particular spatial arrangement of substituents on aromatic rings, which is related to the structure-activity relationship demonstrated by the compound class. Generally, this substitution arrangement is denoted by a numbering system; however, numbering systems are generally not consistent between different ring systems. In six-membered aromatic systems, the Petition 870210054926, dated 06 / 18 / 2021, page 50 / 238 46 / 198 spatial arrangements are specified by the common nomenclature for replacement 1,4, meta for replacement 1,3 and ortho for replacement 1,2 as shown below. ortho

[00098] All structures covered in a claim are chemically practicable, meaning that the structure described by any combination or subcombination of optional substituents intended to be cited in the claim is physically capable of existing with at least some stability as can be determined from the laws of structural chemistry and experimentation. Structures that are not chemically practicable are not found in a set of claimed compounds.

[00099] In general, substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that Petition 870210054926, dated 06 / 18 / 2021, page 51 / 238 47 / 198 can be linked to a carbon atom (or others) substituted include F, Cl, Br, I, OR', OC(O)N(R')2, CN, CF3, OCF3, R', O, S, C(O), S(O), methylenediol, ethylenedioxy, N(R')2, SR', SOR', SO2R', SO2N(R') SO3R', C(O)R', C(O)C(O)R', C(O)CH2C(O)R', C(S)R', C(O)OR', OC(O)R', C(O)N(R')2, OC(O)N(R')2, C(S)N(R')2, (CH2)O-2NHC(O)R', (CH2)O-2N(R')N(R')2, N(R')N(R')C(O)R', N(R')N(R')C(O)OR', N(R')N(R')CON(R')2, N(R')SO2R', N(R')SO2N(R')2, N(R')C(O)OR', N(R')C(O)R', N(R')C(S)R', N(R')C(O)N(R')2, N(R')C(S)N(R')2, N(COR')COR', N(OR')R', C(=NH)N(R')2, C(O)N(OR')R', or C(=NOR')R', where R' can be hydrogen or a carbon-based moiety, and the carbon-based moiety can be further substituted. [000100] Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups, as well as other substituted groups, also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles. The substituents of the substituted groups may be further substituted by alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and alkynyl groups as defined herein, which may be further substituted. For example, a C1-4 alkyl group can be replaced by an amide, and the amide can be further replaced by another C14 alkyl group, which can be further replaced. [000101] Substituted ring groups, such as substituted ethyl, heterocyclyl, and heteroaryl groups, also include fused ring systems in which a bond to a hydrogen atom is replaced by a bond to a carbon atom. Therefore, the groups Petition 870210054926, dated 06 / 18 / 2021, p. 52 / 238 48 / 198 substituted aryl, heterocyclyl and heteroaryl groups may also be substituted by alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, and alkynyl groups as defined herein, which may be further substituted. [000102] As used here, the term heteroatoms refers to non-carbon and non-hydrogen atoms capable of forming covalent bonds with carbon, and are not otherwise limited. Typical heteroatoms are N, O, and S. When sulfur (S) is referred to, it is understood that sulfur may be in any of the oxidation states in which it is found, including sulfoxides (RS(O)-R') and sulfones (RS(O)2-R'), unless the oxidation state is specified; therefore, the term sulfone covers only the sulfone form of sulfur; the term sulfide covers only the sulfide form (RS-R') of sulfur. When phrases such as heteroatoms selected from the group consisting of O, NH, NR', and S, or [variable] are O, S . . . If these terms are used, it is understood that they encompass all oxidation states of sulfur sulfide, sulfoxide, and sulfone. [000103] Alkyl groups include straight-chain or branched-chain alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms (C1-20 alkyl), and typically from 1 to 12 carbon atoms (C112 alkyl) or, in some embodiments, from 1 to 8 carbon atoms (C1-8 alkyl) or, in some embodiments, from 1 to 4 carbon atoms (C1-4 alkyl) or, in some embodiments, from 1 to 3 carbon atoms (C1-3 alkyl). Examples of straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched-chain alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups may be substituted one or more times by any of the groups listed above. Petition 870210054926, dated 06 / 18 / 2021, p. 53 / 238 49 / 198 example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The n-hydroxy C1-4 alkyl group represents a C1-4 alkyl substituted with a terminal hydroxy group. [000104] Cycloalkyl groups are alkyl groups that form a ring structure, which may be substituted or unsubstituted. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms varies from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups also include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted by linear or branched chain alkyl groups as defined above.Representative substituted cycloalkyl groups may be mono-substituted or multi-substituted, such as, but not limited to, disubstituted 2,2-, 2,3-, 2,4-, 2,5- or 2,6-cyclohexyl groups or mono-, di- or tri-substituted norbonyl or cycloheptyl groups, which may be substituted, for example, by amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. [000105] The terms carbocyclic and carbocycle denote a ring structure where the ring atoms are carbon atoms. In some embodiments, the carbocycle has from 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is 4, 5, 6, or 7. Except where specifically indicated otherwise, the carbocyclic ring may be substituted by up to N substituents where N is the size of the carbocyclic ring with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. [000106] The (cycloalkyl)alkyl groups, also denoted as Petition 870210054926, dated 06 / 18 / 2021, p. 54 / 238 50 / 198 Cycloalkylalkyl groups are alkyl groups as defined above where a hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkyl group as defined above. [000107] Alkenyl groups include branched-chain and cyclic alkyl groups as defined above, except that there is at least one double bond between two carbon atoms. Therefore, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -CH=CH(CH3), -CH=C(CH3)2, -C(CH3)=CH2, -C(CH3)=CH(CH3), -C(C H2CH3)=CH2, vinyl, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others. [000108] The term cycloalkenyl alone or in combination denotes a cyclic alkenyl group where at least one double bond is present in the ring structure. Cycloalkenyl groups include cycloalkyl groups having at least one double bond between two adjacent carbon atoms. Therefore, for example, cycloalkenyl groups include, but are not limited to, cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. [000109] Cycloalkenyl alkyl groups are alkyl groups as defined above where a hydrogen or carbon bond of the alkyl group is replaced by a bond to a cycloalkenyl group as defined above. [000110] Alkynyl groups include linear or branched chain alkyl groups, except that there is at least one triple bond between two carbon atoms. Therefore, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbon atoms or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to, -C-CH, -CC(CHs), Petition 870210054926, dated 06 / 18 / 2021, p. 55 / 238 51 / 198 CC(CHzCH3), -CH2C CH, -CH2C C(CH<), and -CH2C CjCH^CH^), among others. [000111] Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Therefore, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysynyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6 to 14 carbon atoms in the ring portions of the groups. The term aryl groups includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), and also includes substituted aryl groups that have other groups, including but not limited to alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, attached to one of the ring atoms.Representative substituted aryl groups may be mono-substituted or multi-substituted, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted by groups that include, but are not limited to, those listed above. [000112] Aralkyl groups are alkyl groups as defined above where a hydrogen or carbon bond of an alkyl group is replaced by a bond to an aryl group as defined above. Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups, such as 4-ethylindanyl. The aryl or alkyl portion or both are optionally replaced by other groups, which include, but are not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups. Aralkenyl groups are alkenyl groups as defined above where a hydrogen or carbon bond of an alkyl group is replaced by a bond to an aryl group as defined above. Petition 870210054926, dated 06 / 18 / 2021, p. 56 / 238 52 / 198 [000113] Heterocyclyl groups include aromatic and non-aromatic ring compounds (heterocyclic rings) containing 3 or more ring members, one or more of which consist of a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl groups include from 3 to 20 ring members, while other groups have from 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring system and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are heterocyclyl groups within the meaning contained herein. A heterocyclyl group designated as a C2-heterocyclyl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms, and so on.Similarly, a C4 heterocyclic ring can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so on. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms. A saturated heterocyclic ring refers to a heterocyclic ring containing no unsaturated carbon atoms. [000114] The term heterocyclyl group includes fused ring species that include those fused aromatic and non-aromatic groups. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl, and also includes heterocyclyl groups that have substituents, which include, but are not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups, attached to one of the ring members. A heterocyclyl group as defined in this document may be a heteroaryl group or a partially or fully saturated cyclic group that includes at least one ring heteroatom. Heterocyclyl groups include, but are not limited to Petition 870210054926, dated 06 / 18 / 2021, p. 57 / 238 53 / 198 a, pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. The heterocyclyl groups can be substituted.Representative substituted heterocyclyl groups may be mono-substituted or substituted more than once, which include, but are not limited to, rings containing at least one heteroatom that are mono-, di-, tri-, tetra-, penta-, hexa-substituted, or substituted more than once by substituents such as those listed above, which include, but are not limited to, alkyl, halo, amino, hydroxy, cyano-, carboxy, nitro-, thio-, and alkoxy groups. [000115] Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, one or more of which consist of a heteroatom such as, but not limited to, N, O, and S. A heteroaryl group designated as a C2-heteroaryl can be a 5-membered ring with two carbon atoms and three heteroatoms, a 6-membered ring with two carbon atoms and four heteroatoms, and so on. Similarly, a C4-heteroaryl can be a 5-membered ring with one heteroatom, a 6-membered ring with two heteroatoms, and so on. The number of carbon atoms plus the number of heteroatoms equals the total number of ring atoms.Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, and benzothiazolyl. Petition 870210054926, dated 06 / 18 / 2021, page 58 / 238 54 / 198 benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thiaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl. The terms heteroaryl and heteroaryl groups include fused ring compounds such as those where at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indole, and 2,3-dihydroindole. The term also includes heteroaryl groups that have other groups attached to one or more ring members, which include, but are not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups. Representative substituted heteroaryl groups can be replaced one or more times by groups like those listed previously. [000116] Additional examples of aryl and heteroaryl groups include, but not limited to, phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hidroxy tetrazolyla, N-hidroxy triazolyl, N-hidroxy imidazolyl, antracenyl (1-antracenyl, 2-antracenyl, 3-antracenyl), thiofenyl (2-thienyl, 3-thienyl), furila (2-furila, 3-furila), indolila, oxadiazolila, isoxazolila, quinazolinila, fluorenila, xantenila, isoindanila, benzidrila, acridinila, tiazolila, pyrrolila (2pyrrolila), pirazolila (3-pirazolila), imidazolila (1-imidazolila, 2-imidazolila, 4-imidazolila, 5-imidazolila), triazolila (1,2,3-triazol-1-ila, 1,2,3-triazol-2-il, 1,2,3-triazol-4-ila, 1,2,4-triazol-3-il), oxazolila (2-oxazolila, 4-oxazolila, 5oxazolila), tiazolila (2-thiazolila, 4-thiazolila, 5-thiazolila), piridila (2-piridila, 3-piridila, 4-piridila), pirimidinila (2-pirimidinila, 4-pirimidinila, 5-pirimidinila, 6-pirimidinila), pirazinila, piridazinil (3-piridazinila, 4-piridazinila, 5-piridazinila),quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-quinolyl, 8-quinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b] furanyl, 4benzo[b]furanyl, 5-benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b], Petition 870210054926, of 18 / 06 / 2021, p. 59 / 238 55 / 198 furanyl), 2,3-di-hydro-benzo[b]furanyl (2-(2,3-di-hydro-benzo[b]furanyl), 3-(2,3-di-hydro-benzo[b]furanyl), 4-(2,3-di-hydro-benzo[b]furanyl), 5-(2,3-di-hydro-benzo[b]furanyl), 6-(2,3-di-hydro-benzo[b]furanyl), 7-(2,3di-hydro-benzo[b]furanyl), benzo[b]thiophenyl (2-benzo[b]thiophenyl, 3benzo[b]thiophenyl, 4-benzo[b]thiophenyl, 5-benzo[b]thiophenyl, 6benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-di-hydro-benzo[b]thiophenyl, (2(2,3-di-hydro-benzo[b]thiophenyl), 3-(2,3-di-hydro-benzo[b]thiophenyl), 4-(2,3di-hydro-benzo[b]thiophenyl), 5-(2,3-di-hydro-benzo[b]thiophenyl), 6-(2,3-dihydro-benzo[b]thiophenyl), 7-(2,3-di-hydro-benzo[b]thiophenyl), indolyl (1indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazolyl (1-indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8-benzimidazolyl),benzoxazolila (1-benzoxazolila, 2-benzoxazolila), benzotiazolila (1-benzotiazolila, 2-benzotiazolila, 4-benzotiazolila, 5benzotiazolila, 6-benzotiazolila, 7-benzotiazolila), carbazolila (1-carbazolila, 2-carbazolila, 3-carbazolila, 4-carbazolila), 5H-dibenz[b,f]azepina (5Hdibenz[b,f]azepin-1-ila, 5H-dibenz[b,f]azepin-2-ila, 5H-dibenz[b,f]azepina3-ila, 5H-dibenz[b,f]azepina-4-ila, 5H-dibenz[b,f]azepin-5-ila), 10,11-dihydro-5H-dibenz[b,f]azepina (10,11-di-hidro-5H-dibenz[b,f]azepin-1-ila, 10,11-di-hidro-5H-dibenz[b,f] azepin-2-ila, 10,11-di-hidro-5H-dibenz[b,f]azepin-3-ila, 10,11-di-hidro-5H-dibenz[b,f]azepin-4-ila, 10,11di-hidro-5H-dibenz[b,f]azepin-5-ila), e similares. [000117] Heterocyclylalkyl groups are alkyl groups as defined above where a hydrogen or carbon bond of an alkyl group is replaced by a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, methyl 2-yl furan, methyl 3-yl furan, methyl 2-yl pyridine (α-picolyl), methyl 3-yl pyridine (β-picolyl), methyl 4-yl pyridine (γ-picolyl), ethyl tetrahydrofuran, and 2-yl indole. Petition 870210054926, dated 06 / 18 / 2021, p. 60 / 238 56 / 198 propyl. The heterocyclylalkyl groups can be substituted on the heterocyclyl portion, on the alkyl portion, or on both. [000118] Heteroarylalkyl groups are alkyl groups as defined above where a hydrogen or carbon bond of an alkyl group is replaced by a bond to a heteroaryl group as defined above. Heteroarylalkyl groups may be substituted on the heteroaryl moiety, on the alkyl moiety, or on both. [000119] As used herein, the term ring system means a portion comprising one, two, three, or more rings, which may be replaced by non-ring groups or by other ring systems, or both, which may be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and where the ring system includes more than a single ring, the rings may be fused, linked, or spirocyclic. The term spirocyclic means the class of structures where two rings are fused onto a single tetrahedral carbon atom, as is well known in the art. [000120] As used herein, the term monocyclic, bicyclic, or polycyclic, aromatic or partially aromatic ring refers to a ring system that includes an unsaturated ring possessing 4n+2 pi electrons, or a partially reduced (hydrogenated) form thereof. The aromatic or partially aromatic ring may include fused, linked, or spiro rings that are not aromatic or partially aromatic. For example, naphthalene and tetrahydronaphthalene are both a monocyclic, bicyclic, or polycyclic, aromatic or partially aromatic ring within the meaning herein. Similarly, for example, a benzo-[2.2.2]-bicyclooctane is also a monocyclic, bicyclic, or polycyclic, aromatic or partially aromatic ring within the meaning herein, containing a phenyl ring fused to a linked bicyclic system. A fully saturated ring Petition 870210054926, dated 06 / 18 / 2021, page 61 / 238 57 / 198 has no double bonds, and is carbocyclic or heterocyclic depending on the presence of heteroatoms within the meaning contained herein. [000121] The term alkoxy refers to an oxygen atom connected to an alkyl group, which includes a cycloalkyl group, as defined above. Examples of linear alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, n-pentyloxy, n-hexyloxy, and the like. Examples of branched alkoxy include, but are not limited to, isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include, but are not limited to, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. [000122] The terms aryloxy and arylalkoxy refer, respectively, to an aryl group attached to an oxygen atom and an aralkyl group attached to the oxygen atom in the alkyl moiety. Examples include, but are not limited to, phenoxy, naphthyloxy, and benzyloxy. [000123] As used herein, an acyl group is used to refer to a group containing a carbonyl moiety where the group is attached through the carbonyl carbon atom. The carbonyl carbon atom is also attached to another carbon atom, which may be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl or similar group. In the special case where the carbonyl carbon atom is attached to a hydrogen atom, the group is a formyl group, an acyl group as defined herein. An acyl group may include from 0 to about 12-20 additional carbon atoms attached to the carbonyl group. An acyl group may include double or triple bonds within the meaning contained herein. An acryloyl group is an example of an acyl group. An acyl group may also include heteroatoms within the meaning contained herein.A nicotinoyl (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning contained herein. Other examples include acetyl, benzoyl, and phenylacetyl groups. Petition 870210054926, dated 06 / 18 / 2021, page 62 / 238 58 / 198 pyridylacethyl, cinnamoyl, and acryloyl and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is called a haloacyl group. An example is a trifluoroacetyl group. [000124] The term amine includes primary, secondary, and tertiary amines having, for example, the formula N(group)3 where each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include, but are not limited to, RNH2, for example, alkylamines, arylamines, alkylarylamines; R2NH where each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines, and the like; and R3N where each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term amine also includes ammonium ions as used here. [000125] An amino group is a substituent of the form -NH2, -NHR, NR2, -NR3+, where each R is independently selected, and protonated forms of each of these. Consequently, any compound substituted with an amino group can be viewed as an amine. [000126] An ammonium ion includes the unsubstituted ammonium ion NH4+, but, except where otherwise specified, also includes any protonated or quaternized forms of amines. Therefore, trimethylammonium hydrochloride and tetramethylammonium chloride are ammonium ions, and amines, within the meaning contained herein. [000127] The term amide (or amido) includes C and N amide groups, that is, C(O)N R'R'' and NR'C(O)R groups, respectively. The OR' and R'' of the C amide can join to form a heterocyclic ring with the nitrogen atom. Therefore, amide groups include, but are not limited to, carbamoyl groups (-C(O)NH2) and formamide groups (-NHC(O)H). A carboxamido group is a group of the formula C(O)NR2, where R can be Petition 870210054926, dated 06 / 18 / 2021, page 63 / 238 59 / 198 H, alkyl, aryl, etc. [000128] The term urethane (or carbamyl) includes urethane N and O groups, that is, NRC(O)OR and OC(O)NR2 groups, respectively. [000129] The term sulfonamide (or sulfonamido) includes sulfonamide S and N groups, that is, SO2NR2 and NRSO2R groups, respectively. Therefore, sulfonamide groups include, but are not limited to, sulfamoyl groups (-SO2NH2). [000130] The term amidine or amidino includes groups of the formula C(NR)NR2. Typically, an amidino group is -C(NH)NH2. [000131] The term guanidine or guanidino includes groups of the formula NRC(NR)NR2. Typically, a guanidino group is NHC(NH)NH2. [000132] Halo, halogen, and halide include fluorine, chlorine, bromine, and iodine. [000133] The terms comprising, including, having, composed of, are terms not limited according to the usage in question, and do not exclude the existence of additional elements or components. In a claim element, the use of the forms comprising, including, having, or composed of means that any element comprised, endowed, included, or composed of is not necessarily the only element covered by the subject matter of the clause containing such words. [000134] A salt as well known in the art includes an organic compound, such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example, sodium, potassium, and the like; with ammonium salts such as NH4+ or the cations of various amines, which include tetraalkyl ammonium salts such as tetramethylammonium and alkyl ammonium salts such as tromethamine salts, or other cations such as trimethylsulfonium, and the like. A Petition 870210054926, dated 06 / 18 / 2021, page 64 / 238 A pharmaceutically acceptable or pharmacologically acceptable salt is a formate salt from an ion that has been approved for human consumption and is generally non-toxic, such as a chlorine salt or a sodium salt. A zwitterion is an internal salt such as one that can be formed in a molecule having at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can be present in a zwitterionic form. A zwitterion is a salt within the meaning contained herein. The compounds of the present invention can take the form of salts. The term salts refers to addition salts of free acids or free bases that are compounds of the invention. The salts can be pharmaceutically acceptable salts. The term pharmaceutically acceptable salt refers to salts that have toxicity profiles within a range that provides utility in pharmaceutical applications.Pharmaceutically unacceptable salts may, however, possess properties such as high crystallinity, which are useful in the practice of the present invention, such as, for example, being useful in the synthesis, purification or formulation of compounds of the invention. [000135] Suitable pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydrodiodic, nitric, carbonic, sulfuric, and phosphoric acids. Suitable organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids; examples of these include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, and embonic acids. Petition 870210054926, dated 06 / 18 / 2021, page 65 / 238 61 / 198 (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates. [000136] Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metal salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts produced from basic amines such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine) and procaine. Examples of pharmaceutically acceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicines, these salts may be useful, for example, as intermediates in the synthesis of compounds, for example, in their purification by recrystallization.All these salts can be prepared by conventional means from the corresponding compound by reacting, for example, the appropriate acid or base with the compound. The term pharmaceutically acceptable salts refers to addition salts of non-toxic inorganic or organic acids and / or bases, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated here by reference. [000137] Non-limiting examples of potential salts of this invention include, but are not limited to, hydrochloride, citrate, glycolate, fumarate, malate, tartrate, mesylate, esilate, cinnamate, isethionate, sulfate, phosphate, diphosphate, nitrate, hydrobromide, iodide, succinate, formate, Petition 870210054926, dated 06 / 18 / 2021, page 66 / 238 62 / 198 acetate, dichloroacetate, lactate, p-toluenesulfonate, pamitate, pidolate, pamoate, salicylate, 4-aminosalicylate, benzoate, 4-acetamidobenzoate, glutamate, aspartate, glycolate, adipate, alginate, ascorbate, besylate, camphorate, camphorsulfonate, camsylate, caprate, caproate, cyclamate, lauryl sulfate, edisylate, gentisate, galactarate, gluceptate, gluconate, glucuronate, oxoglutarate, hippurate, lactobionate, malonate, maleate, mandalate, napsilate, napadisylate, oxalate, oleate, sebacate, stearate, succinate, thiocyanate, undecylenate, and xinafoate. [000138] A hydrate is a compound that is present in a composition with water molecules. The composition may include water in stoichiometric amounts, such as a monohydrate or a dihydrate, or it may include water in random amounts. As used here, the term hydrate refers to a solid form, that is, a compound in aqueous solution, although it may be hydrated, it is not a hydrate as used here. [000139] A homologue of a compound of the invention is a compound having one or more atoms of the compound substituted by an isotope of that atom. For example, homologues include compounds with deuterium in place of some hydrogen atoms of the compound, such as the compounds of the invention where the methyl groups of the isopropoxy portion of Formulas IR and IS are completely or partially deuterated (e.g., (D3C)2C-O-). Isotopic substitutions that can be made in the formation of homologues of the invention include non-radioactive (stable) atoms such as deuterium and carbon 13, as well as radioactive (unstable) atoms such as tritium, carbon 14, iodine 123, iodine 125, etc. [000140] A solvate is a similar composition except that a solvent other than water replaces the water. For example, methanol or ethanol can form an alcoholate, which again can be stoichiometric or non-stoichiometric. Depending on its use in Petition 870210054926, dated 06 / 18 / 2021, p. 67 / 238 63 / 198 question, the term solvate refers to a solid form, that is, a compound in solution in a solvent, although it can be solvated, it is not a solvate as used in this context. [000141] A prodrug, as well known in the art, is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemical agents in the patient's body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as found in the bloodstream of humans and other mammals. [000142] Any compound that can be converted in vivo to the active drug by chemical or biochemical transformations functions as a prodrug. Prodrugs of the claimed compounds are covered by this. [000143] Some examples of prodrugs within the scope of this invention include: i. If the compound contains a hydroxyl group, the hydroxyl group can be modified to form an ester, carbonate, or carbamate. Examples include acetate, pivalate, methyl and ethyl carbonates, and dimethylcarbamate. Esters can also be derived from amino acids such as glycine, serine, or lysine. ii. If the compound contains an amine group, the amine group can be modified to form an amide. Examples include acetamide or derivatization with amino acids such as glycine, serine, or lysine. [000144] Certain compounds of the invention and their salts may be present in more than one crystalline form, and the present invention includes each crystalline form and mixtures thereof. Furthermore, the compounds Petition 870210054926, dated 06 / 18 / 2021, page 68 / 238 The compounds of the present invention, 64 / 198, may be present in non-solvated forms, as well as solvated with pharmaceutically acceptable solvents such as water to form hydrates or adducts with alcohols such as C1-4-alkanols, and the like. Furthermore, the compounds of this invention may be isolated in association with solvent molecules by crystallization from the evaporation of a suitable solvent. These solvents include, but are not limited to, toluene, tetrahydrofuran, dioxane, dimethylformamide, acetonitrile, acetates such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, propyl acetate and isopropyl acetate, ethers such as diethyl ether and ethyl ether, alcohols such as methanol, ethanol, 1- or 2-butanol, 1- or 2-propanol, pentanol, and dimethyl sulfoxide. In general, a description of a compound by its structure or name is considered to encompass the compound in any form (e.g., by itself, as a hydrate, solvate, or otherwise in a mixture). [000145] Furthermore, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, the claims for X being bromine and the claims for X being bromine and chlorine are fully described. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also described in terms of any combination of individual members or subgroups of members of Markush groups. Therefore, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, the... Petition 870210054926, dated 06 / 18 / 2021, page 69 / 238 65 / 198 claims for X being bromine and Y being methyl are fully described. Combination Compositions and Treatments [000146] The S1Pi compounds, their pharmaceutically acceptable salts or hydrolyzable esters of the present invention can be combined with a pharmaceutically acceptable vehicle to provide pharmaceutical compositions useful for the treatment of biological conditions or disorders noted herein in mammalian species, and more preferably in humans. The particular vehicle employed in these pharmaceutical compositions may vary depending on the type of administration desired (e.g., intravenous, oral, topical, suppository, or parenteral). [000147] In the preparation of compositions in oral liquid dosage forms (e.g., suspensions, elixirs, and solutions), typical pharmaceutical media such as water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, and the like may be employed. Similarly, when preparing oral solid dosage forms (e.g., powders, tablets, and capsules), vehicles such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like may be employed. [000148] Another aspect of an embodiment of an invention provides compositions of the compounds of the invention, alone or in combination with another S1Pi inhibitor or another type of therapeutic agent, or both. As presented in this document, the compounds of the invention include stereoisomers, tautomers, solvates, hydrates, salts including pharmaceutically acceptable salts, and mixtures thereof. Compositions containing a compound of the invention can be prepared using conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy, Petition 870210054926, dated 06 / 18 / 2021, p. 70 / 238 66 / 198 19th Ed., 1995, incorporated herein by reference. Compositions may appear in conventional forms, for example, capsules, tablets, aerosols, solutions, suspensions, or topical applications. [000149] Typical compositions include a compound of the invention and a pharmaceutically acceptable excipient which may be a vehicle or a diluent. For example, the active compound will generally be mixed with a vehicle, or diluted by a vehicle, or enclosed within a vehicle which may be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a vehicle, or when the vehicle serves as a diluent, this may be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound may be absorbed in a granular solid vehicle, for example, contained in a sachet.Some examples of suitable vehicles are water, saline solutions, alcohols, polyethylene glycols, ethoxylated polyhydroxy castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl esters of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the vehicle or diluent may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax. [000150] The formulations may be mixed with auxiliary agents that do not react detrimentally with the active compounds. These additives may include wetting agents, emulsifiers and suspending agents, salt to influence osmotic pressure, buffers and / or preservatives for coloring substances, agents Petition 870210054926, dated 06 / 18 / 2021, page 71 / 238 67 / 198 sweeteners or flavoring agents. The compositions may also be sterilized if desired. [000151] The route of administration may be any route that effectively delivers the active compound of the invention that inhibits the enzymatic activity of focal adhesion kinase to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, for example, rectal, depot, subcutaneous, intravenous, intraurethral, ​​intramuscular, intranasal, ophthalmic solution or an ointment, with the oral route being preferred. [000152] For parenteral administration, the vehicle will typically comprise sterile water, although other ingredients that aid solubility or serve as preservatives may also be included. In addition, injectable suspensions may also be prepared, in which case appropriate liquid vehicles, suspending agents and the like may be used. [000153] For topical administration, the compounds of the present invention can be formulated using tasteless moisturizing bases such as ointments or creams. [000154] If a solid vehicle is used for oral administration, the preparation may be in the form of a tablet, contained in a hard gelatin capsule in powder form or in pellet form, or it may be in the form of a lozenge or pill. If a liquid vehicle is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule, or sterile injectable liquid as a suspension or aqueous or non-aqueous liquid solution. [000155] Injectable dosage forms generally include aqueous suspensions or oily suspensions that can be prepared using a suitable dispersant or wetting agent and a suspending agent. Injection forms may be in solution phase or in the form of a suspension, which is Petition 870210054926, dated 06 / 18 / 2021, p. 72 / 238 68 / 198 prepared with a solvent or diluent. Acceptable solvents or vehicles include sterile water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils may be used as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di-, or triglycerides. [000156] For injection, the formulation may also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze-dried, spin-dried or spray-dried powders, amorphous powders, granules, precipitates, or particulates. For injection, formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof. Compounds may be formulated for parenteral administration by injection such as bolus injection or continuous infusion. A unit dosage form for injection may be in ampoules or multi-dose containers. [000157] The formulations of the invention can be designed to provide rapid, sustained, or delayed release of the active ingredient after administration to the patient using procedures well known in the art. Therefore, the formulations can also be formulated for controlled release or for slow release. [000158] The compositions contemplated by the present invention may include, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended-release form to provide a prolonged storage and / or distribution effect. Therefore, the formulations may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously as depot injections. These implants may Petition 870210054926, dated 06 / 18 / 2021, page 73 / 238 69 / 198 employ inert materials known as silicones and biodegradable polymers, for example, polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). [000159] For nasal administration, the preparation may contain a compound of the invention that inhibits the enzymatic activity of focal adhesion kinase, dissolved or suspended in a liquid vehicle, preferably an aqueous vehicle, for aerosol application. The vehicle may contain additives such as solubilizing agents, for example, propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens. [000160] For parenteral administration, injectable solutions or suspensions are particularly suitable, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. [000161] Dosage forms may be administered daily, or more than once a day, such as two or three times a day. Alternatively, dosage forms may be administered less frequently than daily, such as every other day, or weekly, if a prescribing physician deems it appropriate. [000162] One embodiment of the invention also encompasses prodrugs of a compound of the invention that, upon administration, undergo chemical conversion by metabolic or other physiological processes before becoming active pharmacological substances. Conversion by metabolic or other physiological processes includes, without limitation, enzymatic (e.g., enzymatically catalyzed specific) and non-enzymatic (e.g., general or acid- or base-induced specific) chemical transformation of the prodrug into the active pharmacological substance. In general, these prodrugs will be Petition 870210054926, dated 06 / 18 / 2021, page 74 / 238 70 / 198 functional derivatives of a compound of the invention that are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. [000163] In another embodiment, methods are provided for manufacturing a composition of a compound described herein that includes formulating a compound of the invention with a pharmaceutically acceptable vehicle or diluent. In some embodiments, the pharmaceutically acceptable vehicle or diluent is suitable for oral administration. In some embodiments, the methods may further include the step of formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable vehicle or diluent is suitable for parenteral administration. In some embodiments, the methods further include the step of lyophilizing the composition to form a lyophilized preparation. [000164] The compounds of the invention can be used therapeutically in combination with i) one or more other S1Pi inhibitors and / or ii) one or more other types of protein kinase inhibitors and / or one or more other types of therapeutic agents that can be administered orally in the same dosage form, in a separate oral dosage form (e.g., sequentially or non-sequentially) or by injection together or separately (e.g., sequentially or non-sequentially). [000165] Consequently, in another embodiment, the invention provides combinations, which comprise: a) a compound of the invention as described herein; and b) one or more compounds comprising: i) other compounds of the present invention, ii) other medicaments adapted for the treatment of Petition 870210054926, dated 06 / 18 / 2021, page 75 / 238 71 / 198 a disease for which S1Pi activation is medically indicated, for example, multiple sclerosis, transplant rejection, or adult respiratory distress syndrome. [000166] Combinations of the invention include mixtures of compounds (a) and (b) in a single formulation and compounds (a) and (b) as separate formulations. Some combinations of the invention may be packaged as separate formulations in a kit. In some embodiments, two or more compounds of (b) are formulated together while one compound of the invention is formulated separately. [000167] Dosages and formulations for other agents to be used, where applicable, will be as stipulated in the latest edition of Physicians' Desk Reference, incorporated herein by reference. Treatment Methods [000168] In certain embodiments, the present invention encompasses orally bioavailable compounds that specifically agonize S1Pi without binding to (S1P2, S1P3 and S1P4), or having significant specificity with respect to (S1P5), other EDG receptors. A selective S1Pi agonist can be used to treat diseases with autoimmune components, with hyperactive immune response, angiogenesis or inflammatory components, but would not be limited to such conditions. Selective S1Pi agonists offer advantages over current therapies by increasing the therapeutic window due to reduced toxicity resulting from binding to other EDG receptors. [000169] In certain embodiments, the present invention encompasses compounds that bind with high affinity and specificity to the S1Pi receptor in an agonistic manner. By binding the S1Pi receptor to the agonist, signaling proceeds through Gai, inhibiting cAMP generation by adenylate cyclase. [000170] In certain embodiments, the present invention provides a method for activating or agonizing (i.e., having an effect) Petition 870210054926, dated 06 / 18 / 2021, page 76 / 238 72 / 198 agonist, to act as an agonist) a sphingosine-1-phosphate receptor of the subtype, such as S1Pi, with a compound of the invention. The method involves bringing the receptor into contact with an appropriate concentration of an inventive compound to cause receptor activation. The contact can occur in vitro, for example, in performing an assay to determine the S1P receptor activation activity of an inventive compound submitted to an experiment related to a regulatory approval submission. [000171] In certain embodiments, the method for activating an S1P receptor, such as S1Pi, can also be performed in vivo, i.e., within the living body of a mammal, such as a human patient or a test animal. The inventive compound can be delivered to the living organism via one of the routes described above, for example, orally, or it can be delivered locally within the body tissues, for example, by injecting a tumor into the organism. In the presence of the inventive compound, receptor activation occurs, and its effect can be studied. [000172] One embodiment of the present invention provides a method of treating a disease in a patient for which activation of an S1P receptor, such as S1Pi, is medically indicated, wherein the patient is administered the inventive compound at a dosage, frequency, and duration to produce a beneficial effect on the patient. The inventive compound can be administered by any suitable means, examples of which are described above. PREPARATION FOR CERTAIN MODALITIES Scheme 7: [000173] Reagents: (i) KH2PO4, H2O2, NaClO2, CH3CN; (ii) Petition 870210054926, dated 06 / 18 / 2021, p. 77 / 238 73 / 198 H2NNHCSNH2, POCh; (iii) CuBr2, isoamyl nitrite, CH3CN. Esciuema 2: [000174] Reagents: (i) R1-boronic acid, K2CO3, Pd(PPh3)4, DME, H2O; (ii) NBS, DMF. Scheme 3: [000175] Reagents: (i) R1-l, Pd(PPh3)2Cl2, THF; (ii) Br2, AcOK, AcOH. Scheme 4: OH [000176] Reagents: (i) R1-Br, K2CO3, Pd(PPh3)4, DME, H2O; (ii) NBS, DMF. Scheme 5: [000177] Reagents: (i) (S)-2-methyl-CBS-oxazaborolidine, BH3-Me2S, toluene, DCM; (ii) PG-CI, (where PG is the protecting group), for example, TBSCI, imidazole, DMF; (iii) bis(pinacolate)diboron, PdCI2(dppf).CH2CI2, KOAc, 1,4-dioxane. [000178] The (S)-enantiomer was prepared in the same manner as described in Scheme 5 by using (R)-2-methyl-CBSoxazaborolidine in Step i. The racemic material can be prepared analogously using NaBH4 as the reducing agent in Step i. Scheme 6: Petition 870210054926, dated 06 / 18 / 2021, page 78 / 238 74 / 198 [000179] Reagents: (i) (R)-2-methylpropane-2-sulfinamide, NaBH4, THF, toluene; (ii) 4N HCl, 1,4-dioxane; (iii) PG = di-tert-butyldicarbonate, triethylamine, DCM; (iv) bis(pinacolate)diboron, PdCl2(dppf).CH2Cl2, KOAc, 1,4-dioxane. [000180] The (S)-enantiomer was prepared in the same manner as described in Scheme 6 by using (S)-2-methylpropane-2-sulfinamide in Step i. Scheme 7: CN CN [000181] Reagents: (i) K2CO3, Pd(PPh3)4, DME, H2O; (ii) NaO / Pr, / PrOH; (iii) deprotection, for example, TBAF, THF or HCl, 1,4-dioxane. [000182] The (S)-enantiomers were prepared in the same manner as described in Scheme 7 by using (S)-tert-butyldimethyl ((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane in Step i. Racemic indanol was prepared in the same manner using racemic tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane in Step i. Petition 870210054926, dated 06 / 18 / 2021, page 79 / 238 75 / 198 [000183] Reagents: (i) K2CO3, Pd(PPh3)4, DME, H2O; (ii) NaO / Pr, / PrOH; (iii) 4N HCl, 1,4-dioxane; (iv) (a) R'-LG or R-LG, where LG represents a leaving group, K2CO3, CH3CN; (b) R3-CO2H or R4CO2H, HOBt, EDC, DMF or R3-COCl or R4-CO2H, TEA, DCM; (c) R3SO2Cl or R5-SO2Cl, TEA, DCM; (d) R4-CHO, HOAc, NaBH4 or NaCNBH3 or Na(OAc)3BH, MeOH; (e) R3-OCOCl or R4-OCOCl, DIEA, DMF; (f) HN(R7R7), CDI, TEA, DCM; (g) H2NSO2NH2, D, dioxane; (h) dimethyloxirane, D, EtOH; (x) (a) If R' or R = H, then reactions (ix)(ad) can be carried out; (b) If R' or R contains an ester, then (i) hydrolysis of NaOH, EtOH or (ii) reduction of NaBH4, MeOH can be carried out; (c) If R' or R contains an acid, then couplings of HN(R7R7), HOBt, EDC, DMF can be carried out; (d) If R' or R contains a suitable active alkene, then Michael additions of HN(R7R7), DMF can be carried out. [000184] The (S)-enantiomers were prepared in the same manner as described in Scheme 8 by using (S)-tert-butyl (4-(4,4,5,5 Petition 870210054926, dated 06 / 18 / 2021, p. 80 / 238 76 / 198 tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate in Step i. Scheme 9: CN CN [000185] Reagents: (i) (3-cyano-4-isopropoxyphenyl) boronic acid, K2CO3, Pd(PPh3)4, DME, H2O; (ii) (R)-, (S)-, or tert-butyldimethyl((4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1yl)oxy)silane, K2CO3, Pd(PPh3)4, DME, H2O; (iii) TBAF, THF. Scheme 10: [000186] Reagents: (i) (ii) (R)-, (S)-, or tert-butyldimethyl((4-(4,4,5,5tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy) racemic silane, K2CO3, Pd(PPh3)4, DME, H2O; (ii) (3-cyano-4isopropoxyphenyl)boronic acid, K2CO3, Pd(PPh3)4, DME, H2O; (iii) TBAF, THF. EXAMPLES General Methods [000187] Ή NMR (400 MHz) and 13C NMR (100 MHz) were obtained in deuterated chloroform (CDCI3), deuterated methanol (CD3OD) or dimethyl sulfoxide (DMSO) solutions. The NMR spectra were processed using Mestrec 5.3.0 and 6.0.1. The 13C NMR peaks in parentheses are two rotamers of the same carbon. Mass spectra (LCMS) were obtained using an Agilent 1100 / 6110 HPLC system equipped with a Thompson ODS-A, 100A, 5 μm (50 x 4.6 mm) column using water with 0.1% formic acid as mobile phase A, and acetonitrile with 0.1% formic acid as mobile phase B. The gradient was 20-100% with mobile phase B for 2.5 min, then maintained. Petition 870210054926, dated 06 / 18 / 2021, p. 81 / 238 77 / 198 at 100% for 2.5 minutes. The flow rate is 1 mL / min. Except where otherwise indicated, the LCMS data provided use this method. For more hydrophobic compounds, the following gradient was used, indicated as Method 1: 40-95% for 0.5 min, held at 95% for 8.5 min, then back to 40% for 2 min, with a flow rate of 1 mL / min. The final compounds were checked for purity using Method 2: 5% for 1 min, 5-95% for 9 min, then held at 95% for 5 min, with a flow rate of 1 mL / min. Method 3: 20-100% for 2.5 min then held at 100% for 4.5 min, with a flow rate of 1 mL / min. Enantiomeric excess was determined by integrating peaks that were separated on a Chiralpak AD-H column, 250 x 4.6 mm, at a flow rate of 1 mL / min and an isocratic mobile phase. Except where otherwise indicated, the chiral data provided utilize this method.Alternatively, chiral separations were performed under the following conditions, denoted as Chiral Method 1: Chiralpak AY-H column, 250 x 4.6 mm at a flow rate of 1 mL / min and an isocratic mobile phase. Chiral Method 2: Chiralcel OZ-3, 150 x 4.6 mm at a flow rate of 1 mL / min and an isocratic mobile phase. The pyridine, dichloromethane (DCM), tetrahydrofuran (THF), and toluene used in the procedures are from Aldrich Sure-Seal bottles maintained under nitrogen (N2). All reactions were magnetically stirred and temperatures are external reaction temperatures. Chromatographies were performed using a Combirápida Rf flash purification system (Teledyne Isco) equipped with silica gel (SiO2) columns from Redisep (Teledyne Isco).Preparative HPLC purifications were performed on a Varian ProStar / PrepStar system using water containing 0.05% trifluoroacetic acid as mobile phase A, and acetonitrile with 0.05% trifluoroacetic acid as mobile phase B. The gradient is 10-80% with mobile phase B for 12 min, maintained at 80% for 2 min, and then returned to 10% for 2 min with flow rate. Petition 870210054926, dated 06 / 18 / 2021, p. 82 / 238 78 / 198 CN of 22 mL / min. Other methods similar to this were employed. Fractions were collected using a Varian Prostar fraction collector and evaporated using a Savant SpeedVac Plus vacuum pump. Compounds with salinable centers were presumed to be the trifluoroacetic acid (TFA) salt. Microwave heating was performed using a Biotage Initiator microwave reactor equipped with Biotage microwave vessels. The following abbreviations were used: ethyl acetate (EA), triethylamine (TEA), diethylamine (DEA), hydroxybenzotriazole (HOBt), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), isopropanol (IPA), dimethylformamide (DMF), dimethylacetamide (DMA). Norit is activated charcoal. Experimental Procedures 3-Cyano-4-fluorobenzoic acid CN [000188] To a solution of 3-cyano-4-fluorobenzaldehyde (45 g, 301 mmol) in CH3CN (450 mL) was added monobasic potassium phosphate (24 g, 176 mmol) in water (225 mL) and 30% hydrogen peroxide in water (30 mL). The reaction mixture was cooled to 0°C and sodium chloride (60 g, 663 mmol) in water (450 mL) was added dropwise over 2 h. The resulting yellow suspension was stirred at room temperature until oxygen production ceased (4 h). Sodium sulfite (30 g, 238 mmol) in water (100 mL) was added and the reaction mixture stirred for 1 h. The reaction was rapidly cooled with 2N HCl (500 mL) and the resulting solid was filtered and washed with water. The aqueous phase was extracted with EA (2 x 500 mL). The combined organic layers were washed with brine (200 mL), dried over MgSO4, concentrated, and combined with the collected solid to yield a total of 48.5 g (97%) of 3-cyano-4-acid. Petition 870210054926, dated 06 / 18 / 2021, page 83 / 238 79 / 198 crude fluorobenzoic as a white solid. A LCMS-ESI (m / z) calculated for C8H4FNO2: 165.0; obteve 166.1[M+H]+, tr = 2.54 min.1H NMR (400 MHz, DMSO) δ 13.60 (s, 1H), 8.41 (dd, J = 6.3, 2.1 Hz, 1H), 8.30 (ddd, J = 8.8, 5.3, 2.2 Hz, 1H), 7.66 (t, J = 9.0 Hz, 1H). 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (TDZ INT-1) [000189] To a stirred mixture of 3-cyano-4-fluorobenzoic acid (37.3 g, 225 mmol) and thiosemicarbazide (22.6 g, 248 mmol) was added POCh (148 mL) at 0°C. The reaction mixture was stirred at 0°C for 1 h and then heated to 85°C for 6 h. The resulting yellow solution was cooled to room temperature and concentrated to 50% by volume. The residue was cooled to 0°C and water (300 mL) was added dropwise. (Caution: exothermic and violent reaction with gas evolution). The mixture was heated to 90°C for 1 h, then cooled to room temperature. EA (300 mL) was added and the reaction mixture was stirred for 10 min before filtration. The collected solid was dispersed in water (270 mL), cooled to 0°C, and neutralized with a 50% aqueous NaOH solution at pH 8.The resulting solid was filtered, carefully washed with water, and dried under high vacuum to provide 26 g (52%) of 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 as a pale yellow solid that was used in the next experiment without purification. The calculated LCMSESI (m / z) for C9H5FN4S: 220.0; obtained 221.1 [M+H]+, tr = 2.44 min, Ή NMR (400 MHz, DMSO) δ 8.29 (dd, J = 6.1,2.3 Hz, 1H), 8.19 (ddd, J = 8.9, 5.2, 2.4 Hz, 1H), 7.64 (t, J = 9.0 Hz, 1H), 7.58 (s, 2H), 13C NMR (101 MHz, DMSO) δ 169.82, 164.25, 161.68, 133.68, 131.65, 128.96, 117.96, 113.77, 101.59. [000190] 5-(3,4-Diethoxyphenyl)-1,3,4-thiadiazol-2-amine TDZ INT-2 was synthesized in a similar manner to 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-amine. Petition 870210054926, dated 06 / 18 / 2021, page 84 / 238 80 / 198 fluorobenzonitrile TDZ INT-1 using 3,4-diethoxybenzoic acid. A LCMS-ESI (m / z) calculated for C12H15N3O2S: 265.3; obteve 266.1, [M+H]+, iR= 2.58 min,1H NMR (400 MHz, DMSO) δ 7.45 - 7.31 (m, 1H), 7.23 (dd, J = 8.3, 2.1 Hz, 1H), 7.06 (d, J = 8.4 Hz, 1H), 4.31 - 3.94(m,4H), 3.4(s,2H), 1.42(qd,J=6.8,3.3Hz,6H). 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (TDZ I NT-3) F CN [000191] To a stirred solution of 5-(5-amino-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-1 (25 g, 113 mmol) and copper bromide (30.4 g, 136 mmol) in CH3CN (400 mL), isoamyl nitrite (15.9 g, 136 mmol) was added, and the mixture was stirred at room temperature for 5 h. The reaction was split between EA (2 x 250 mL) and 1N HCl (250 mL). The combined organic extracts were washed with brine, dried over MgSO4, and concentrated. The crude product was crystallized from EA to provide 23.5 g (73%) of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 as a pale yellow solid. The LCMS-ESI (m / z) calculated for: CgHsBrFNsS: 284.1; obtained 285.9 [M+H]+, tR = 3.27 min, Ή NMR (400 MHz, DMSO) δ 8.58 (dd, J = 6.0, 2.3 Hz, 1H), 8.40 (ddd, J = 8.9, 5.1, 2.4 Hz, 1H), 7.76 (t, J = 9.0 Hz, 1H);13C NMR (101 MHz, DMSO) δ 168.61,162.47, 140.32, 134.88, 133.38, 126.13, 117.88, 112.91.[000192] 2-Bromo-5-(3,4-diethoxyphenyl)-1,3,4-thiadiazole TDZ INT-4 was synthesized in a manner similar to that described for the synthesis of 2bromo-5-(3,4-diethoxyphenyl)-1,3,4-thiadiazole TDZ INT-3 using 5-(3,4diethoxyphenyl)-1,3,4-thiadiazol-2-amine. A LCMS-ESI (m / z) calculated for: Ci2Hi3BrN2O2S: 328.0; yielded 329.1 [M+H]+, fa = 2.58 min,1H NMR (400 MHz, CDCh) δ 7.47 (d, J = 2.1 Hz, 1H), 7.25 (d, J = 2.1 Hz, 1H), 6.84 (d, J = 2.1 Hz, 1H), J= 8.9, 7.0 Hz, 4H), 1.42 (t, J= 7.0 Hz, 6H). 2-fluoro-5-(thiazol-2-yl)benzonitrile (THZ INT-1) Petition 870210054926, of 18 / 06 / 2021, p. 85 / 238 81 / 198 Br [000193] A solution of 2-bromothiazole (25 g, 153.4 mmol), (3-cyano-4-fluorophenyl)boronic acid (25.3 g, 153.3 mmol), K2CO3 (63.6 g, 460 mmol) and 3:1 DME / H2O (205 mL) was purged with N2 for 1 h before the addition of Pd(PPhs)4 (9.2 g, 7.9 mmol). The mixture was further degassed with N2 for 5 min and then heated to 85°C for 7 h under N2. Upon cooling, the reaction mixture was diluted with EA (250 mL), washed with water (200 mL) and brine (200 mL), and dried over MgSO4. The reaction mixture was filtered and concentrated to obtain a beige solid. The crude product was purified by recrystallization of 20% EA / hexanes to provide 22 g (71%) of 2-fluoro-5-(thiazol-2yl)benzonitrile THZ INT-1 as a pale yellow solid.LCMS-ESI (m / z) calculated for C10H5FN2S: 204.2; obtained 205.0 [M+H]+, ír = 3.26 min,1H NMR (400 MHz, CDCl3) δ 8.21 - 8.16 (m, 1H), 8.15 - 8.08 (m, 1H), 7.86 - 7.81 (m, 1H), 7.36 - 7.32 (m, 1H), 7.27 - 7.21 (m, 1H),13C NMR (101 MHz, CDCI3) δ 164.31, 162.22, 143.73, 132.68, 131.28, 128.34, 119.94, 116.98, 113.10. 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile (THZ INT-2) [000194] To 2-fluoro-5-(thiazol-2-yl)benzonitrile (21.8 g, 106.7 mmol) in anhydrous DMF (200 mL) recrystallized N-bromosuccinimide (22.7 g, 128 mmol) was added. The reaction mixture was stirred at room temperature for 23 h under N2. The reaction mixture was basified with 1N NaOH and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated. Petition 870210054926, dated 06 / 18 / 2021, page 86 / 238 82 / 198 to produce an orange oil. The crude product was purified by fast silica gel chromatography (20% EA / Hexanes) to yield 21 mg (70%) of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 as a half-white solid. The calculated LCMS-ESI (m / z) for CiOH4BrFN2S: 283.1; obtained 284.9 [M+H]+, fR = 3.82 min,1H NMR (400 MHz, CDCI3) δ 8.15 (dd, J = 5.9, 2.3 Hz, 1H), 8.08 (ddd, J = 8.8, 4.9, 2.3 Hz, 1H), 7.78 (d, J = 4.8 Hz, 1H), 7.31 (t, J = 8.6 Hz, 1H), (S)-4-bromo-2,3-dihydro-1H-inden-1 -ol (IND INT-1) OH Br Br [000195] To a 100 mL three-necked flask fitted with an internal thermometer and an addition funnel, (R)-(+)-2-methylaCBS-oxazaborolidine (1.6 mL, 1M solution in toluene) and boranedimethyl sulfide (150 µL) were added under N2. The reaction was stirred at room temperature for 10 min, then diluted with DCM (10 mL). Boranedimethyl sulfide (6.0 mL) was added and the reaction cooled to -20°C. A solution of 4-Bromo-2,3-dihydro-1H-inden-1-one (2.5 g, 11.8 mmol) in DCM (10 mL) was added dropwise over 20 minutes while maintaining the reaction temperature at -20 ± 5°C. The reaction was stirred for 2 h after the addition was complete, then rapidly cooled by the dropwise addition of MeOH (10 mL). The reaction mixture was diluted with MeOH (20 mL) and the solvent distilled at atmospheric pressure. MeOH (30 mL) was added in two portions and the distillation was repeated twice.All solvent was evaporated to obtain a solid which was purified by silica gel column chromatography (EA / hexanes) and recrystallization from 5:1 hexane / EA (30 mL) to give 1.56 g (62%) of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol as a white powder IND INT-1. The LCMSESI (m / z) calculated for CgHgBrO: 213.1; yielded 196.9 [M-OH]+, Ir = 3.06 min. Ή NMR (400 MHz, CDCb) δ 7.40 (d, J = 7.9 Hz, 1H), 7.33 (d, J = 7.5. Petition 870210054926, dated 06 / 18 / 2021, p. 87 / 238 83 / 198 Hz, 1H), 7.10 (t, J = 7.7 Hz, 1H), 5.29 (dd, J = 12.6, 6.9 Hz, 1H), 3.05 (ddd, J = 16.6, 8.7, 4.6 Hz, 1H), 2.87 - 2.71 (m, 1H), 2.50 (dddd, J = 13.2, 8.4, 7.0, 4.6 Hz, 1H), 1.94 (dddd, J = 13.5, 8.8, 6.6, 5.5 Hz, 1H), 1.80 (d, J = 7.1 Hz, 1H), 13C NMR (101 MHz, CDCh) δ 146.82, 143.50, 131.24, 128.58, 123.21, 120.25, 76.83, 34.69, 31.19, HPLC Chiral: (S)-4-bromo-2,3-dihydro-1H-inden-1-ol was eluted using 10% IPA in hexanes: >99.9% ee, tr= 6.27 min. [000196] (R )-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-2 was prepared analogously using (S )-(-)-2-methyl-CBSoxazaborolidine: 97.6% ee, t Rpara (R )-enantiomer = 5.83 min. (S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tertbutyl)dimethylsilane (IND INT-3) [000197] To a solution of (S)-4-bromo-2,3-dihydro-1H-inden-1-ol IND INT-1 (1.56 g, 7.3 mm) in DMF (5 mL) were added TBDMSCl (1.3 g, 8.7 mmol) and imidazole (1.24 g, 18.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with saturated NaHCOa solution (30 mL) and extracted with EA (2 x 50 mL). The organic layers were washed with water and brine, and dried over MgSO4. The crude product was purified by chromatography (EA / hexane) to give 2.1 g (88%) of (S)-((4-bromo-2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane IND INT-3 as a white solid. The LCMS-ESI (m / z) calculated for C^HaaBrOSi: 327.3; no M+ observed, tr = 5.73 min (Method 2). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 7.8 Hz, 1H), 7.22 (d, J = 7.4 Hz, 1H), 7.07 (t, J = 7.7 Hz, 1H), 5.28 (t, J = 7.1 Hz, 1H), 3.00 (ddd, J = 16.4, 9.1,2.9 Hz, 1H), 2.73 (dt, J = 16.5, 8.3 Hz, 1H), 2.42 (dddd, J = 12.8, 7.0, Hz, 1H), 1.91 (dtd, J = 12.8, 8.9, 7.1 Hz, 1H), 0.98 - 0.88 (m, 9H), 0.14. Petition 870210054926, of 18 / 06 / 2021, p. 88 / 238 84 / 198 (d, J = 7.4 Hz, 6H). [000198] (R)-((4-bromo-2,3-di-hydro-1 H-inden-1-yl)oxy)(tercbutyl)dimethylsilane IND INT-4 was prepared in a similar manner using (R)-4-bromo-2,3-di-hydro-1 H-inden-1-ol. (±)-4-bromo-2,3-di-hydro-1 H-inden-1 -ol (IND INT-5) OH Br Br [000199] To a stirred solution of 4-bromoindanone (3 g, 14.2 mmol) in anhydrous EtOH (30 mL) were added sodium borohydride (0.36 g, 9.5 mmol) and silica gel (2 g) at 0°C. The reaction was stirred at 0°C for 20 min and allowed to stir at room temperature for 2 h. The reaction mixture was rapidly cooled with saturated NaHCO3 solution (10 mL) and concentrated to remove EtOH. The aqueous layer was extracted with EA (3 x 20 mL) and the organic phase was dried over MgSO4. After concentration, the crude product was purified by chromatography (EA / hexane) to yield (±)-4-bromo-2,3-dihydro-1 / - / -inden-1-ol IND INT-5 (2.56 g, 85%) as a white solid. The LCMS-ESI (m / z) calculated for CgHgBrO: 213.07; obtained 195.0 [M-H2O]+, fa = 3.07 min, 1H NMR (400 MHz, CDCI3) δ 7.35 (d, J = 7.9, 1H), 7.27 (d, J = 7.4, 1H), 7.05 (t, J = 7.7, 1H), 5.23 (t, J = 6.2, 1H), 3.00 (ddd, J = 16.6, 8.8, 4.6, 1H), 2.84-2.66 (m, 1H), 2.45 (dddd, J= 13.2, 8.4, 7.0, 4.6, 1H), 1.96 — 1.70 (m, 2H). (S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2,3-di-hydro-1 H-inden-1 -yl)oxy)silane (IND INT-6) Br OTBS Petition 870210054926, dated 06 / 18 / 2021, p. 89 / 238 85 / 198 [000200] A solution of (S)-((4-bromo-2,3-dihydro-1H-inden-1yl)oxy)(tert-butyl)dimethylsilane IND INT-3 (0.2 mg, 0.61 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (0.17 g, 0.67 mmol), and potassium acetate (1.8 g, 0.45 mmol) in anhydrous 1,4-dioxane (4 mL) was degassed by passing N2 through the solution for 10 min. PdCl2(dppf).CH2Cl2 (99 mg, 0.12 mmol) was added and the reaction mixture heated to 85°C overnight. The solvent was removed under vacuum. The residue was dissolved in EA (10 mL) and filtered through celite. The filtrate was washed with water and brine, dried over MgSO4, and filtered. The crude product was purified by chromatography (EA / hexanes) to provide 26 mg (45%) (S)-tert-butyldimethyl((4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1yl)oxy)silane IND INT-6 as a white solid. The LCMS-ESI (m / z) was calculated for C21H35BO3SL 374.4; obtained 245.0 [M-OTBS]+, tr = 6.57 min (Method 1),1H NMR (400 MHz, CDCh) δ 7.66 (d, J = 7.2 Hz, 1H), 7.36 (dd, J = 8.7, 4.3 Hz, 1, 7.9), dd, J = 8.7, 4.3 Hz, 1, 7.9, J 5.4 Hz, 1H), 5.21 (t, J = 7.0 Hz, 1H), 3.26 (ddd, J = 16.9, 8.9, 3.0 Hz, 1H), 2.86 (dt, J = 16.8, 8.3 Hz, 1H), (dtd, J = 12.6, 8.8, 7.0 Hz, 1H), 1.38 - 1.23 (m, 12H), 1.00 - 0.81 (m, 9H), 0.22 - 0.07 (m, 6H),13C NMR (101 MHz, CDCl, 159, δ 145.08, 134.83, 134.75, 126.92, 125.78, 83.39, 76.52, 36.29, 30.78, 25.96, 24.96, 18.28, -4.29, -4.55. [000201] (R)-terc -butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2dioxaborolan-2-yl)-2,3-di-hydro-1H-inden-1-yl)oxy)silane IND INT-7 was prepared in an analogous manner using (R)-(R)-(4-1-b Hinden-1-yl)oxy)( terc -butyl)dimethylsilano IND INT-4. (±)-terc -butyldimethyl((4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-di-hydro-1H-inden-1yl)oxy)silane racemic IND INT-8 was similarly prepared from IND INT-5. General Procedure 1: Coupling of Heterocyclic Bromide to Indanol Boronate Petition 870210054926, dated 06 / 18 / 2021, page 90 / 238 86 / 198 [000202] A 20 mL microwaveable flask was sequentially charged with heterocyclic bromide (1 eq), (R)-(S)- or racemic indanol dioxaborolane (IND INT-6, 7 or 8, 1 eq), DME:H2O (3:1, 0.05 M) and potassium carbonate (3 eq). The mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPhs)4 (0.07 eq) was added and the mixture degassed for a further 2 min. The flask was stoppered and subjected to microwave irradiation at 100°C until the reaction was complete (40-60 min). Additional bromide was added if necessary. The flask was cooled to room temperature, diluted with EA (10 x volume), washed with water and brine, dried in MgSO4, and concentrated. The crude product was purified by silica gel column chromatography (EA / hexanes). (S)-5-(5-( 1-((tert-butyldimethylsilyl)oxy)-2,3-di-hydro-1 H-inden4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile [000203] Prepared using General Procedure Γ. A 20 mL microwave flask was loaded with 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (30 mg, 0.1 mmol), (S)tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-6 (43.6 mg, 0.11 mmol), potassium carbonate (44 mg, 0.32 mmol), and a 3:1 mixture of DME / H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirring solution for 10 min. Pd(PPh3)4 was added and the mixture degassed for a further 2 min. The flask was subjected to microwave irradiation at 100°C for 40 min. The reaction mixture was cooled to room temperature, diluted with EA (10 mL), and washed with water and brine. The organic layer was dried over MgSO4, concentrated, and purified by silica gel chromatography. Petition 870210054926, dated 06 / 18 / 2021, p. 91 / 238 87 / 198 (EA / hexanes) to provide 25 mg (44%) of (S)-5-(5-(1-((tercbutyldimethylsilyl)oxy)-2,3-di-hydro-1 H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2fluorobenzene trilate as a sonyl claridole. A LCMS-ESI (m / z) calculated for C24H26FN3OSSI: 451.15; yielded 452.1 [M+H]+, fa = 4.53 min (Method 1),1H NMR (400 MHz, CDCI3) δ 8.34 - 8.25 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1Hz), 7.49 (d, J = 7.7, Hz - 7.34 (m, 2H), 5.34 (t, J = 7.1 Hz, 1H), 3.46 (ddd, J = 16.8, 9.0, 2.8 Hz, 1H), 3.13 (dt, J = 16.8, 8.3 Hz, 1H), - 1.96 (m, 1H), 0.98 - 0.95 (m, 9H), 0.22-0.17 (m, 6H). [000204] (R)-5-(5-(1 -((terc-butyldimethylsilyl)oxy)-2,3-di-hydro-1 H-inden4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile was prepared in a similar manner using (R)-terc-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2dioxaborolane-2-yl)-2,3-di-hydro-1H-inden-1-yl)oxy)silano IND INT-7. (S)-5-(5-( 1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden4-yl)thiazol-2-yl)-2-fluorobenzonitrile [000205] Prepared using General Procedure 1. A solution of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 (0.12 g, 0.42 mmol), (S)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-6 (0.16 g, 0.42 mmol), potassium carbonate (0.176 g, 1.2 mmol) and a 3:1 mixture of DME / H2O (2 mL) was degassed with N2 for 10 min before the addition of Pd(PPh3)4 (0.034 g, 0.03 mmol). The reaction mixture was degassed with N2 for 2 min and then heated under microwave at 90°C for 1.5 h. Upon cooling, the reaction mixture was diluted with EA (20 mL) and washed with brine (20 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by fast silica gel chromatography (30% EA / hexanes) to produce Petition 870210054926, dated 06 / 18 / 2021, p. 92 / 238 88 / 198 0.116 g (60%) of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1Hinden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile as a white solid. The LCMSESI (m / z) calculated for C25H27FN2OSSi: 450.6; obtained 451.1 [M+H]+, tr = 4.86 min (Method1), Ή NMR (400 MHz, CDCL3) δ 8.30-8.14 (m, 2H), 7.95 (s, 1H), 7.45 (dd, J = 7.0, 0.9, 1H), 7.32 (ddd, J = 23.9, 14.6, 11.0, 3H), 5.32 (t, J = 7.0, 1H), 3.19 (ddd, J = 15.9, 8.8, 2.7, 1H), 2.95 (dt, J = 16.1, 8.1, 1H), 2.59-2.40 (m, 1H), 2.08-1.89 (m, 1H), 0.94 (s, 9H), 0.17 (dd, J = 13.7, 7.8, 6H). [000206] (R )-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden4-yl)thiazol-2-yl)-2-fluorobenzonitrile was prepared in an analogous manner using (R)-tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane. General Procedure 2: Fluorine Displacement with Isopropoxide [000207] To a stirred solution of (R)- or (S)fluorobenzene derivative (1 eq) in IPA (0.02 M) sodium isopropoxide (1.3 eq) was added. The reaction was stirred at 60°C under N2 for 2 h or until the reaction was complete. Upon cooling, the solvent was evaporated to dryness and the product was purified by silica gel column chromatography (EA / hexanes). (S)-5-(5-( 1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile A solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile (21 mg, 0.04 mmol) in IPA (2 mL) was added to sodium isopropoxide (5 mg, 0.06 mmol). The reaction mixture was heated to 60°C for 2 h. Upon cooling, the solvent was evaporated and the product was purified by Petition 870210054926, dated 06 / 18 / 2021, page 93 / 238 89 / 198 a silica-gel column chromatography (EA / hexanes) was performed to provide (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1-hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (15 mg, 68%). The calculated LCMS-ESI (m / z) for C28H34N2O2SSÍ: 491.7, yielded 492.2 [M+H]+, RI = 5.17 min (Method 1). [000209] (F?)-5-(5-(1-((ferc-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile was prepared in an analogous manner using (F?)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile. (S)-5-(5-( 1 -(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-isopropoxybenzonitrile [000210] Prepared using General Procedure 2. To a solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-fluorobenzonitrile (116 mg, 0.25 mmol) in IPA (2 mL) was added sodium isopropoxide (21.1 mg, 0.25 mmol). The reaction mixture was heated at 60°C for 2 h. Upon cooling, the solvent was evaporated and the product was purified by silica gel column chromatography (EA / hexanes) to provide 151 mg (88%) of (S)-5(5-(1-(tert-butyldimethylsiloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile. The calculated LCMS-ESI (m / z) for C28H34N2O2SS1: 490.7, yielded 491.1 [M+H]+, tR = 6.81 min (Method 1). [000211] (F?)-5-(5-(1-(tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-isopropoxybenzonitrile was prepared analogously using (F?)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-fluorobenzonitrile. General Procedure 3: Deprotection of Silyl-protected Indanols [000212] To a stirred solution of (R)- or (S)-protected indanol Petition 870210054926, dated 06 / 18 / 2021, page 94 / 238 90 / 198 silica (1 eq) in anhydrous THF (0.06 M) was added to 1 M tetrabutyl ammonium fluoride (5 eq) in THF and the mixture was stirred at room temperature under N2. Upon completion, the reaction mixture was diluted with EA (10x volume), and carefully washed with NaHCO3, water and brine, dried over MgSCU, and concentrated. The crude product was purified by silica gel column chromatography (EA / hexanes). [000213] Compounds 1-3 and 69-70 were prepared using a sequence of General Procedures 1-3. (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol2-yl)-2-isopropoxybenzonitrile (Compostol) [000214] To a stirred solution of (S)-5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (21 mg, 0.06 mmol) in anhydrous THF (1 mL) was added 1M tetrabutyl ammonium fluoride (0.3 mL, 0.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with EA (10 mL), washed with saturated NaHCO3 and brine, and dried over MgSCU. The product was purified by chromatography (EA / hexanes) to yield 8 mg (81%) of (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 1 as a white solid.A LCMS-ESI (m / z) calculada para C21H19N3O2S: 377,1; obteve 378,1 [M+H]+, fR= 3,67 min,1H RMN (400 MHz, CDCI3) δ 8,28 - 8,07 (m, 2H), 7,86 (d, J = 7,5 Hz, 1H), 7,57 (d, J = 7,5 Hz, 1H), 7,40 (t, J = 7,6 Hz, 1H), 7,08 (d, J = 9,0 Hz, 1H), 5,41 -5,18 (m, 1H), 4,74 (dd, J= 12,2, 6,0 Hz, 1H), 3,48 (ddd, J= 17,1, 8,7, 4,6 Hz, 1H), 3,30 - 3,06 (m, 1H), 2,72 - 2,40 (m, 1H), 2,04 (ddd, J = 13,6, 8,7, 6,5 Hz, 1H), 1,64 (s, 2H), 1,44 (d, J = 6,1 Hz, 5H),13C RMN (101 MHz, CDCI3) δ 167,61, 166,22, 162,23, 147,58, 142,93, 134,04,. Petição 870210054926, de 18 / 06 / 2021, pág. 95 / 238 91 / 198 133,83, 129,81, 128,30, 127,45, 127,09, 123,37, 116,14, 114,45, 104,34, 77,23, 76,71,73,09, 36,24, 31,69, 22,32. [000215] (R)-5-(5-(1-hydroxy-2,3-di-hydro-1 H-inden-4-yl)-1,3,4-thiadiazol2-yl)-2-isopropoxybenzonitrile 2 was prepared in an analogous manner using (R)-5-(5-(1 -((terc-butyldimethylsilyl)oxy)-2,3-di-hydro-1 H-inden-4yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile. (S)-5-(5-(1 -hyd roxy -2,3-di-hydro-1 H-inden-4-yl)thiazol-2-yl)-2isopropoxybenzonitrile (Compound 70) CN CN [000216] Prepared using General Procedure 3. To a solution of crude (S)-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile (0.11 g, 0.22 mmol) in anhydrous THF (3 mL) was added 1.0 M TBAF solution (1.0 mL) in THF. The reaction mixture was stirred at room temperature for 2 h. The solvent was concentrated under vacuum and the residue purified by silica gel chromatography to provide 35 mg (41%) of (S)-5(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 70 as a white solid.LCMS-ESI (m / z): calculated for: C22H20N2O2S: 376.4; obtained 377.1 [M+H]+, ír = 3.66 min,1H NMR (400 MHz, CDCl3) δ 8.14 - 7.89 (m, 2H), 7.82 - 7.62 (m, 1H), 7.35 (dd, J = 7.5, 2.6 Hz, 2H), 7.22 (dd, J = 15.0, 7.5 Hz, 1H), 7.02 6.77 (m, 1H), 5.36-5.08 (m, 1H),4.65 (hept, J = 6.0 Hz, 1H), 3.10 (ddd, J = 16.1, 8.5, 4.6 Hz, 1H), 2.93-2.80 (m, 1H), 2.68-2.54 (m, 1H), 2.44 (dddd, J = 11.7, 8.3, 7.0, 4.7 Hz, 1H), 2.01 - 1.77 (m, 1H), 1.41 - 1.29 (m, 6H),13C NMR (101 MHz, CDCI3) δ 164.98, 161.11, 146.82, 141.23, 140.87, 137.98, 132.11, 131.99, 128.40, 128.03, 127.91, 126.67, 124.62, 116.13, 113.98, 103.76, 76.43, 72.55, 35.89, 30.78, 22.01, Chiral HPLC: (S)-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2. Petition 870210054926, dated 06 / 18 / 2021, p. 96 / 238 92 / 198 isopropoxybenzonitrile was eluted using 15% IPA in hexanes: 100% ee; tr = 24.19 min. [000217] (R )-5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2isopropoxy benzonitrile 69 was prepared in an analogous manner using (R )-5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)2-isopropoxy-benzonitrile: 97% ee, tr for (R )-enantiomer = 47.32 min. (S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide (IND INT-9) O Br [000218] A 2L RB flask dried in an oven was loaded with (S)-2-methylpropane-2-sulfinamide (31.5 g, 260 mmol), titanium tetraethoxide (81 g, 355 mmol), and anhydrous toluene (250 mL). The reaction mixture was heated to 90°C and a solution of 4-bromo-2,3-dihydro-1H-inden-1-one (50.0 g, 236 mmol) in anhydrous toluene was added dropwise over 90 min. The reaction mixture was then stirred at 90°C for 4 hours and then overnight at 70°C. The crude (S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide IND INT-9 was used in the next experiment without purification. The LCMS-ESI (m / z) calculated for CnHwBrNOS: 315.0; obtained 316.0 [M+H]+, tr = 3.65 min. [000219] (R,E )-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide IND INT-10 was prepared analogously using (R )-2-methylpropane-2-sulfinamide. (S)-N-((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2methylpropane-2-sulfinamide (IND INT-11) Petition 870210054926, dated 06 / 18 / 2021, p. 97 / 238 93 / 198 [000220] To a stirred suspension of crude (S,E)-N-(4-bromo-2,3-dihydro-1H-inden-1-ylidene)-2-methylpropane-2-sulfinamide IND INT-9 in toluene (250 mL) under N2, anhydrous THF (250 mL) was added and the reaction mixture was cooled to -78°C. Sodium borohydride (26.8 g, 710 mmol) was added in four portions over 30 min (internal temperature maintained below -65°C). The reaction mixture was stirred at -78°C for 30 minutes before being heated to room temperature for 1 h and continued to be stirred for a further 1 h. The reaction mixture was filtered through Celite to remove Ti salts. The filtrate was treated with EA (500 mL), saturated sodium potassium tartrate (200 mL), and brine (50 mL), and the mixture was stirred at room temperature overnight. The mixture was filtered through Celite and the filtrate dried over MgSO4.The crude product was obtained by concentration to dryness to obtain 46 g (61%) of (S)N-((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-11 as a whitish solid which was used in the next experiment without purification. The LCMS-ESI (m / z) calculated for CnHwBrNOS: 313.0; obtained 314.0 [M+H]+, tr = 3.84 min. [000221] (R )-N-(( R )-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-12 was prepared analogously using (R,E )-N-(4-bromo-2,3-dihydro-1 H-inden-1-ylidene)-2-methylpropane-2-sulfinamide IND INT-10. (S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride (IND INT-13) Petition 870210054926, dated 06 / 18 / 2021, page 98 / 238 94 / 198 [000222] To an agitated suspension of (S)-N-((S)-4-bromo-2,3-dihydro Crude 1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-11 (46 g, 145 mol) in MeOH (100 mL) was added to 4N HCl in dioxane (109 mL) and the yellow suspension was stirred at room temperature for 3 h. The crude reaction was diluted with MeOH (100 mL) and filtered. The filtrate was concentrated and the resulting solid was dispersed in acetonitrile (600 mL) and refluxed for 90 min. The suspension was cooled to 0°C and the filtered solid yielded 25 g (69%) of (S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride IND INT-13, which was used in the next step without purification. The LCMS-ESI (m / z) calculated for C9HwBrN: 211.09; obtained 197.0 [M-NH2]+, tr = 1.76 min, 1H NMR (400 MHz, DMSO) δ 8.76 (s, 2H), 7.71 (d, J = 7.5 Hz, 1H), 7.57 (d, J = 7.9 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 4.80 (s, 1H), 3.06 (ddd, J = 16.9, 8.9, 5.2 Hz, 1H), 2.93 - 2.76 (m, 1H), 2.57 - 2.39 (m, 1H), 2.11 - 1.92 (m, 1H);13C NMR (101 MHz, DMSO) δ 144.12, 141.60, 131.71, 129.02, 124.54, 119.29, 55.30, 31.52, 29.10. [000223] (R)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride IND INT-14 was prepared analogously using (R)-N-((S)-4-bromo-2,3-dihydro-1H-inden-1-yl)-2-methylpropane-2-sulfinamide IND INT-12. (S)-tert-butyl 4-bromo-2,3-dihydro-1H-inden-1-ylcarbamate (IND INT-15) Br Br [000224] Crude (S)-4-bromo-2,3-dihydro-1H-inden-1-amine hydrochloride IND INT-13 (16.6 g, 66 mmol) in DCM (140 mL) at 0°C were Petition 870210054926, dated 06 / 18 / 2021, page 99 / 238 95 / 198 added triethylamine (14.8 g, 146 mmol) and di-tert-butyl dicarbonate (16.0 g, 73 mmol). The reaction was stirred at room temperature overnight. The reaction was diluted with DCM (50 mL) and washed with water and brine. The organic layers were dried over MgSO4 and the product purified by crystallization of 10% EA / hexanes to provide 14 g (70%) of (S)-tert-butyl 4-bromo-2,3-dihydro-1-Hinden-1-ylcarbamate IND INT-15 as a whitish solid.A LCMS-ESI (m / z) calculated for CuHwBrNO2: 312.2; obtained 197.0 [MNH2Boc]+, tr = 3.94 min,1H NMR (400 MHz, CDCh) δ 7.38 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), (dd, J = 15.9, 7.9 Hz, 1H), 4.78 (d, J = 7.6 Hz, 1H), 2.99 (ddd, J = 16.5, 9.0, 3.4 Hz, 1H), 2.81 (dt, J = 16.5, 8.2 Hz, 1H), 1H), 1.94 - 1.71 (m, 1H), 1.47 (d, J = 5.2 Hz, 9H),13C NMR (101 MHz, CDCh) δ 120.64, 80.10, 57.21, 33.71, 31.82, 28.86; Chiral HPLC: (S)-tert-butyl 4-bromo-2,3-di-hydro-1 Hinden-1-ylcarbamate was eluted using 2 % IPA in hexanes: >99.9% ee, tr = 11.08 min. [000225] (R)-terc -butyl 4-bromo-2,3-di-hydro-1 H-inden-1-ylcarbamate IND INT-16 was similarly prepared from hydrochloride of (R )-4-bromo-2,3-di-hydro-1H-inden-1-amine IND-14: IND-amine > 99% in para. (R)- enantiomer = 9.98 min. (S)-tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)2,3-dihydro-1H-inden-1-ylcarbamate (IND INT-17) [000226] A solution of (S)-tert-butyl 4-bromo-2,3-dihydro-1-Hinden-1-ylcarbamate IND INT-15 (13.1 g, 42 mmol), 4,4,4',4',5,5,5',5' Petition 870210054926, dated 06 / 18 / 2021, pp. 100 / 238 96 / 198 octamethyl-2,2'-bi(1,3,2-dioxaborolane) (11.7 g, 46 mmol) and potassium acetate (12.3 mg, 125 mmol) in anhydrous 1,4-dioxane (100 mL) was degassed by passing N2 through the solution for 30 min before the addition of PdCk(dppf).CH2Cl2 (6.8 g, 8.3 mmol). The reaction mixture was heated to 85°C for 8 h. The solvent was removed under vacuum and the residue was dissolved in EA (500 mL) and filtered through celite. The filtrate was washed with water and brine, dried over MgSO4, and purified by chromatography (EA / hexanes) to provide 13 g (87%) of (S)tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-hinden-1-ylcarbamate IND INT-17 as a white solid.A LCMS-ESI (m / z) calculated for C20H30BNO4: 359.2; obteve 382.2[M+Na]+, tr = 4.26 min.1H NMR (400 MHz, CDCh) δ 7.66 (d, J = 7.3 Hz, 1H), 7.39 (d, J = 7.5 Hz, 1H), 7.19 (t, J = 7.4 Hz, 1H), 5.14 (dd J = 15.8, 7.8 Hz, 1H), 4.69 (d, J = 8.7 Hz, 1H), 3.23 (ddd, J = 17.0, 8.8, 3.5 Hz, 1H), 2.94 (dt, J = 16.6, 8.2 Hz, 1H), 2.53 (ddd, J = 11.4.1H), 8.0, 3.9 Hz, 1H), 1.73 (ddd, J = 16.4, 12.8, 8.6 Hz, 1H), 1.46 (s, 9H), 1.36 - 1.25 (m, 12H),13C NMR (101 MHz, CDCla) δ 156.21, 150.64. 143.43, 135.37, 127.25, 126.43, 83.95, 79.78, 56.19, 34.60, 31.57, 28.88, 25.37, 25.34. [000227] (R)-tert -butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)2,3-di-hydro-1 H-inden-1-ylcarbamate IND INT-18 foi prepared in analogous manner using (R)-tert -butyl 4-bromo-2,3-di-hydro-1 H-inden1-ylcarbamate IND INT-16. General Procedure 4: Coupling of Heterocyclic Bromates to Indane Amine [000228] A reaction pressure flask was sequentially charged with heterocyclic bromide (1 eq), indanoamine protected by (R)- or (S)-Boc (1 eq), DME:H2O (3:1, 0.07 M), and potassium carbonate (3 eq). The mixture was degassed by bubbling N2 gas through the stirring solution for 20 min. Then, Pd(PPha)4 (0.07 eq) was added and the mixture was degassed for a further 5 min. The flask Petition 870210054926, dated 06 / 18 / 2021, page 101 / 238 97 / 198 of the reaction was tightly sealed and the mixture was heated to 85°C for 12–24 h. The reaction was cooled to room temperature, diluted with water (2x volume), and stirred for 30 min. The resulting solid was filtered, washed with hexanes, and dried under high vacuum. The crude product was purified by silica gel column chromatography (EA / hexanes) or used in the next experiment without purification. (S)-tert-butyl (4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)~ 2,3-dihydro-1 H-inden-1 -yl)carbamate [000229] Prepared using General Procedure 4. A suspension of 5-(5-bromo-1,3,4-thiadiazol-2-yl)-2-fluorobenzonitrile TDZ INT-3 (1.5 g, 5.3 mmol), (S)-tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3dihydro-1H-inden-1-yl)carbamate IND INT-17 (1.9 g, 5.3 mmol) and potassium carbonate (2.2 g, 16 mmol) in DME:H2O (3:1.70 mL) was degassed with N2 for 20 min before the addition of Pd(PPh3)4 (0.43 g, 0.3 mmol). The mixture was degassed with N2 for 5 min and the suspension was heated under N2 at 85°C for 12 h. Upon cooling, the reaction mixture was diluted with water (150 mL) and the mixture was stirred for 30 min. The resulting solid was filtered, washed with water, and dried under high vacuum to provide 2.3 g (100%) of crude (S)-tert-butyl (4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-I)-2,3-dihydro-1H-inden-1-yl)carbamate as a light brown solid which was used in the next experiment without purification.A LCMS-ESI (m / z) calculated for C23H21FN4O2S: 436.1; obtained 459.1 [M+Na]+, tR= 4.19 min. [000230] (R)-terc-butyl (4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)2,3-di-hydro-1 H-inden-1-yl)carbamate was prepared in a similar manner using (R)-terc-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)2,3-di-hydro-1 H-inden-1-yl)carbamate IND INT-18. Petition 870210054926, of 18 / 06 / 2021, p. 102 / 238 98 / 198 (C)-terc-butyl (4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1 H-inden-1 -yl)carbamate CN CN [000231] Prepared using General Procedure 4. A solution of 5-(5-bromothiazol-2-yl)-2-fluorobenzonitrile THZ INT-2 (2.0 g, 7.0 mmol), (S)-tert-butyl (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate IND INT-17 (2.5 g, 7.0 mmol), potassium carbonate (2.9 g, 21 mmol) and a 3:1 mixture of DME / H2O (30 mL) was degassed with N2 for 10 min before the addition of Pd(PPha)4 (0.57 g, 0.005 mmol). The mixture was degassed with N2 for a further 2 min and the suspension was heated under nitrogen at 80°C for 12 h. Upon cooling, the reaction mixture was diluted with EA (20 mL) and washed with brine (20 mL). The combined organic layers were dried with MgSO4, filtered, and concentrated. The crude product was purified by fast silica gel chromatography (30% EA / hexanes) to yield 3.0 g (83%) of (S)-tert-butyl (4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate as a white solid.LCMS-ESI (m / z) calculated for C24H22FN3O2S: 435.5; obtained 436.1 [M+H]+, tR= 4.14 min,1H NMR (400 MHz, CDCI3) δ 8.20 (m, 2H), 7.93 (s, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.32 (m, 3H), 5.26 (m, 1H), 4.76 (d, J= 8.4 Hz, 1H), 3.09 (m, 2H), 2.65 (ddd, J= 12.5, 8.3, 4.6 Hz, 1H), 1.84 (dq, J= 12.9, 8.5 Hz, 1H), 1.48 (s, 9H). (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate CN CN [000232] Prepared using General Procedure 2. To a solution of (S)-tert-butyl (4-(5-(3-cyano-4-fluorophenyl)-1,3,4-thiadiazol-2-yl)-2,3-di Petition 870210054926, dated 06 / 18 / 2021, p. 103 / 238 99 / 198 hydro-1H-inden-1-yl)carbamate (2.5 g, 5.7 mmol) in IPA (30 mL) was added to sodium isopropoxide (0.61 g, 7.4 mmol). The reaction mixture was heated to 60°C for 4 h. Upon cooling, the mixture was concentrated to 50% by volume and the suspension was cooled to 0°C. The resulting solid was filtered and dried under high vacuum to give 1.14 g (42%) of (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate as a whitish solid.A LCMS-ESI (m / z) calculated for C26H28N4O3S: 476.2; obteve 477.2 (M+H), tR= 4.12 min,1H NMR (400 MHz, CDCh) δ 8.26 - 8.04 (m, 2H), 7.82 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.09 (d, J = 9.0 Hz, 1H), 5.38 5.08 (m, 1H), 4.94 - 4.62 (m, 1H), 3.54 - 3.32 (m, 1H), 3.21 (s, 1H), 2.80 -2.59 (m, 1H), 1.97-1.74 (m,1H), 1.52-1.35(m,15H),13C NMR (101 MHz, CDCI3) δ 166.93, 165.54, 161.59, 155.65, 145.84, 142.05, 133.28. 128.71, 127.59, 126.64, 126.33, 122.72, 115.54, 113.86, 103.69, 79.59, 72.50, 60.35, 55.73, 33.78, 31.27, 28.39. 21.74. [000233] (R)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol2-yl)-2,3-di-hydro-1 H-inden-1-yl) carbamate foi prepared in analogous manner using (R)-tert-butyl (4-(5-(3-cyano-4-fluorophenyl)-1,3,4thiadiazol-2-yl)-2,3-di-hydro-1 H-inden-1-yl)carbamate. (S)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3di-hydro-1 H-inden-1 -yl)carbamate [000234] Prepared using General Procedure 2. To a solution of (S)-tert-butyl (4-(2-(3-cyano-4-fluorophenyl)thiazol-5-yl)-2,3-dihydro-1-hinden-1-yl)carbamate (2.5 g, 5.7 mmol) in IPA (50 mL) was added sodium isopropoxide (0.61 g, 7.4 mmol). The reaction mixture was heated to 60°C for 4 h. Upon cooling, the mixture was Petition 870210054926, dated 06 / 18 / 2021, p. 104 / 238 100 / 198 concentrated to 50% by volume and the suspension was cooled to 0°C. The resulting solid was filtered and dried under high vacuum to provide 2.66 g (98%) of (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate. The LCMS-ESI (m / z) calculated for C27H29N3O3S: 475.1; obtained 476.2 (M+H), tR= 4.30 min,1H NMR (400 MHz, CDCI3) δ 8.19 - 8.05 (m, 2H), 7.89 (s, 1H), 7.43 (s, 1H), 7.39 7.28 (m, 2H), 7.04 (d, J= 8.9 Hz, 1H), 5.39-5.15 (m, 1H), 4.73 (s, 2H), 3.20 - 2.94 (m, 2H), 2.69 - 2.57 (m, 1H), 1.94 - 1.77 (m, 1H), 1.49 (s, 9H), 1.44 (d, J= 6.1 Hz, 6H). General Procedure 5: Preparation of Heterocyclic Indanoamines [000235] To a stirred suspension of indanoamine protected by (R)- or (S)-Boc (1 eq) in 1,4-dioxane (0.2 M), 4N of HCl in 1,4-dioxane (10 eq) were added and the mixture was heated to 55°C until the reaction was complete (3-5 h). The reaction was cooled to room temperature and diluted with diethyl ether. The resulting solid was filtered and dried under vacuum to obtain the pure product as a hydrochloride salt. [000236] Compounds 4 to 6 and 71 to 72 were prepared using the sequential application of General Procedures 4, 2, and 5. (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (Compound 4) CN CN [000237] Prepared using General Procedure 5. To a stirred solution of (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.1 g, 2.3 mmol) in 1,4-dioxane (10 mL) was added 4N HCl solution in 1,4-dioxane (10 mL). The reaction mixture was stirred at 55°C for 2.5 h. Upon cooling to 0°C, the reaction mixture was diluted with diethyl ether (100 mL) and the resulting solid was filtered and dried to provide 980 mg Petition 870210054926, dated 06 / 18 / 2021, p. 105 / 238 101 / 198 (96%) hydrochloride of (S)-5-(5-(1-amino-2,3-di-hydro-1H-inden-4-yl)1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 4 as a branched solid. A LCMS-ESI (m / z) calculated for C21H20N4OS, 376.1; obtained 377.1 (M+H), tr = 2.35 min,1H NMR (400 MHz, DMSO) δ 8.64 8.51 (m, 3H), 8.41 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 2.3 Hz, 1H), 8.32 (dd, J = 8.9, 2.4, Hz, J = 199). 7.4 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.59 - 7.49 (m, 2H), 4.95 (dt, J = 12.2, 6.1 Hz, 1H), 4.84 (s, 1H), 3.54 - 3.32 (m, 3.3H), 3.15 (m, 1H), 2.65 - 2.53 (m, 1H), 2.12 (ddd, J = 13.9, 5.6, 3.0 Hz, 1H), 1.37 (dd, J = 10.4, 6.1 Hz, 6H),13C NMR (10.1Hz, δ 166.61, 166.11, 161.5, 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 11.5, 12.15. 72.43, 54.75, 31.48, 30.12, 21.74, Chiral HPLC: hydrochloride of (S )-5-(5-(1-amino-2,3-di-hydro-1H-inden-4-yl)-1,3,4thiadiazol-2-yl)-2-isopropoxypoxy using phosphoylated 30% EtOH in hexanes plus 0.1% DEA: 99.0% ee, tr = 34.2 min. [000238] (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl) 1,3,4-thiadiazol-2-yl)-2 isopropoxybenzonitrile hydrochloride 5 was prepared in an analogous manner using (R)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate: >99.9% ee, tr = 28.8 min. (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride (Compound 71) [000239] Prepared using General Procedure 5. To a stirred solution of (S)-tert-butyl (4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (1.0 g, 2.1 mmol) in 1,4-dioxane (5 mL) were added 4N of HCl solution in 1,4-dioxane (5 mL). The reaction mixture was stirred at 55°C for 2.5 h. Upon cooling to 0°C, the reaction mixture was diluted with diethyl ether (50 Petition 870210054926, dated 06 / 18 / 2021, page 106 / 238 102 / 198 mL) and the resulting solid was filtered, washed with ether (20 mL), and dried to provide 0.86 g (100%) of (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 71. The LCMSESI (m / z) calculated for C22H21N3OS: 375.1; obtained 376.2 (M+H), tr = 2.45 min, 1H NMR (400 MHz, DMSO) δ 8.64 (d, J = 3.6 Hz, 2H), 8.30 (d, J = 2.3 Hz, 1H), 8.23 ​​(dd, J = 8.9, 2.4 Hz, 1H), 8.21 (s, 1H), 7.70 (dd, J = 7.6, 2.6 Hz, 2H), 7.45 (dd, J = 8.4, 5.4 Hz, 2H), 4.91 (dt, J = 12.2, 6.1 Hz, 1H), 4.85 - 4.58 (m, 1H), 3.36 - 3.21 (m, 1H), 3.21 - 3.04 (m, 1H) 143.05, 141.73, 134.16, 133.45, 129.74, 128.26, 127.84, 126.47, 122.33, 115.79, 115.20, 102.53, 72.43, 54.75, 31.48, 30.12, 21.74.Chiral HPLC: (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride was eluted in 8% EtOH / hexanes: >99.9% ee, tr = 67.15 min (Chiral Method 1). [000240] (R)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 72 was prepared analogously using (R)-tert-butyl(4-(5-(3-cyano-4-isopropoxyphenyl)thiazol-2yl)-2,3-dihydro-1H-inden-1-yl)carbamate: 99.0% ee, tr for (R)enantiomer = 62.18 min. General Procedure 6. Preparation of Indano Amides via Acid Coupling [000241] To the suitable acid (1 eq) in DMF (0.05 M) were added HOBt (1.3 eq), and EDC (1.3 eq). The reaction was stirred at room temperature for 0.5 h or until the acid was fully activated. (R)- or (S)-indaneamine (1 eq) was added in a portion and the reaction was stirred at room temperature for 12 h. The crude reaction mixture was subjected to purification by preparative HPLC. Products containing Boc-protected amine side chains were further treated with 4N HCl in 1,4-dioxane and Petition 870210054926, dated 06 / 18 / 2021, page 107 / 238 103 / 198 heated to 55°C for 2 h. The reaction mixture was diluted with diethyl ether and filtered to provide the desired products as hydrochloride salts. [000242] Compounds 7 to 13, 49, 73, 74, 77 - 86 were prepared using General Procedure 6. (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-di-hidro-1H-inden-1-yl)-2-hidroxyacetamida (Compound 7) [000243] Prepared using General Procedure 6. A solution of 2-hydroxyacetic acid (4 mg, 0.05 mmol), HOBt (8.8 mg, 0.06 mmol), EDC (12.5 mg, 0.06 mmol) and DIEA (15 mg, 0.11 mmol) in DMF (1 mL) was stirred for 30 min before the addition of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride in DMF (0.5 mL). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was subjected to preparative HPLC to yield 10 mg (50%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide 7 as a white solid.A LCMSESI (m / z) calculada para: C23H22N4O3S: 434,1; obteve 435,1 [M+H]+, tr = 3,11 min,1H RMN (400 MHz, CDCh) δ 8,19 (dd, J = 8,9, 2,3 Hz, 1H), 8,12 (d, J = 2,2 Hz, 1H), 7,79 (d, J = 7,6 Hz, 1H), 7,42 (d, J = 7,5 Hz, 1H), 7,34 (t, J = 7,6 Hz, 1H), 7,09 (d, J = 9,0 Hz, 1H), 6,85 (d, J = 8,5 Hz, 1H), 5,71 - 5,46 (m, 1H), 4,76 (dt, J = 12,2, 6,1 Hz, 1H), 4,21 (s, 2H), 3,46 (ddd, J = 17,0, 8,7, 3,6 Hz, 1H), 3,30 - 3,09 (m, 1H), 2,69 (ddd, J = 16,6, 8,3, 4,0 Hz, 1H), 2,08 - 1,80 (m, 2H), 1,46 (d, J = 6,1 Hz, 6H),13C RMN (101 MHz, CDCh) δ 167,44, 166,23, 162,20, 145,53, 142,82, 133,89, 133,79, 129,53, 128,28, 127,20, 126,93, 123,12, 116,03, 114,38, 104,22, 73,06, 62,72, 54,46, 33,91,31,98, 22,24. Petição 870210054926, de 18 / 06 / 2021, pág. 108 / 238 104 / 198 [000244] (R)-N-(4-(5-(3-cyano-4-isopropoxifenil)-1,3,4-tiadiazol-2-il)2,3-di-hidro-1H-inden-1-il)-2-hidróxiacetamida 8 foi preparada de maneira análoga utilizando cloridrato de (F?)-5-(5-(1-amino-2,3-di-hidro1 H-inden-4-iI)-1,3,4-tiadiazol-2-il)-2-isopropoxibenzonitrila 5. (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1 H-inden-1 -yl)-2-hidroxyacetamida (Compound 73) [000245] Prepared using General Procedure 6. A solution of 2-hydroxyacetic acid (2 mg, 0.02 mmol), HOBt (4.8 mg, 0.06 mmol), EDC (7.0 mg, 0.06 mmol) and DIEA (7.7 mg, 0.06 mmol) in DMF (1 mL) was stirred for 30 minutes before the addition of (S)-5-(2(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 71 in DMF (0.5 mL). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was subjected to preparative HPLC to yield 5 mg (58%) of ((S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyacetamide 73 as a white solid. The calculated LCMS-ESI (m / z) for: C24H23N3O3S: 433.2; yielded 434.1 [M+H]+, tR = 3.11 min. General Procedure 7. Preparation of Indano Amides via Acid Chlorides [000246] To a stirred solution of (R)- or (S)-indanoamine hydrochloride (1 eq) in anhydrous DCM (0.03 M) was added triethylamine (3 eq) followed by suitable acid chloride (1.5 eq). The reaction mixture was stirred overnight at room temperature. The solvent was evaporated and the product was purified by preparative HPLC. [000247] Compounds 14, 15, 75, 76, 87, and 88 were prepared using General Procedure 7. (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl) Petition 870210054926, dated 06 / 18 / 2021, page 109 / 238 105 / 198 2,3-dihydro-1H-inden-1-yl)acetamide (Compound 14) [000248] Prepared using General Procedure 7: To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 4 hydrochloride (15 mg, 0.03 mmol) in anhydrous DCM (1 mL) was added triethylamine (11 mg, 0.1 mmol) followed by acetyl chloride (4.2 mg, 0.05 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude mixture purified by preparative HPLC to provide (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)acetamide 14. The LCMS-ESI (m / z) calculated for: C23H22N4O2S: 418.2; obtained 419.3 [M+H]+, fR= 3.34 min.1H NMR (400 MHz, CDCh) δ 8.20 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.45 (d, J = 7.5 Hz, 36 Hz), (t, J = 7.6 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 5.83 (d, J = 8.4 Hz, 1H), 5.57 (q, J = 7.9 Hz, 1H), 4.76 (dt, J= 12.2, 6.1, Hz, Hz, 1H), 17.1,8.8, 3.8 Hz, 1H), 3.28-3.15 (m, 1H), 2.75-2.62 (m, 1H), 2.07 (s, 3H), 1.98-1.80 (m, 1H), 1.46 (d, J= 6.1 Hz, 1H), MHz, CDCI3) δ 170.36, 167.43, 166.14, 162.16, 145.92, 142.83, 133.89, 133.77, 129.44, 128.23, 116.05, 114.36, 104.23, 73.03, 55.00, 34.03, 31.95, 23.92, 22.24. [000249] (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-di-hydro-1H- inden-1-yl)acetamide 15 was similarly prepared using hydrochloride (R)-5-(5-(1-amino-2,3-di-hydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 5 . (S)-N-(4-(2-(3-cyano-4-isopropoxyphenii) thiazol-5-yl)-2,3-dihydro-1 H-inden-1 -yl)-2-methoxyacetamide (Compound 76) Petition 870210054926, dated 06 / 18 / 2021, page 110 / 238 106 / 198 [000250] Prepared using General Procedure 7: To a stirred solution of (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 71 (15 mg, 0.03 mmol) in anhydrous DCM (1 mL) was added triethylamine (11 mg, 0.1 mmol) followed by 2-methoxyacetyl chloride (11.8 mg, 0.1 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the crude mixture was purified by preparative HPLC to provide (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-methoxyacetamide 76. The calculated LCMS-ESI (m / z) for C25H25N3O3S: 447.2; obtained 448.1 [M+H]+, tr = 3.70 min. General Procedure 8. Preparation of Indane Carbamates [000251] To a stirred solution of (R)- or (S)-indanoamine (1 eq) in DCM (0.03M) TEA (3 eq) and the appropriate carbon chloride (1.5 eq) were added at room temperature. The reaction was stirred at room temperature for 4 h. The solvent was evaporated and the pure product isolated by precipitation with water or preparative HPLC. [000252] Compounds 16, 68, 89, and 90 were prepared using General Procedure 8. (S)-methyl (4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2yl)-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 16) [000253] Prepared using General Procedure 8. To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (15 mg, 0.03 mmol) and TEA (11 mg, 0.1 mmol) in DCM (1 mL) methyl chloroformate was added. Petition 870210054926, dated 06 / 18 / 2021, page 111 / 238 107 / 198 (10 mg, 0.1). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and water (2 mL) was added. The resulting solid was filtered, washed with water, and dried under high vacuum to provide 12 mg (92%) of (S)-methyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)carbamate 16 as a white solid. The calculated LCMS-ESI (m / z) for C23H22N4O3S: 434.1; yielded 435.3 [M+H]+, tr = 3.69 min. (S)-methyl (4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate (Compound 90) [000254] Prepared using General Procedure 8. To a stirred solution of (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4yl)thiazol-5-yl)-2-isopropoxybenzonitrile 71 hydrochloride (15 mg, 0.03 mmol) and TEA (11 mg, 0.1 mmol) in DCM (1 mL) methyl chloroformate (10 mg, 0.1 mL) was added. The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and water (2 mL) was added. The resulting solid was filtered, washed with water, and dried under high vacuum to provide 6 mg (51%) of (S)-methyl(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 90 as a white solid. The calculated LCMS-ESI (m / z) for C24H23N3O3S: 433.2; yielded 434.1 [M+H]+, tr = 3.86 min. General Procedure 9. Alkylation of Indane Amines [000255] To a solution of (R)- or (S)-indaneamine in CH3CN (0.2 M) were added K2CO3 (3 eq) and the appropriate alkyl halide (1.2 eq). In some cases, TEA (3 eq) and DMF (0.1 M) were used. The mixture was heated to 80-95°C until the starting material was consumed or dialkylation of the amine became predominant. If necessary, additional alkyl halide is added to drive the reaction. The mixture of Petition 870210054926, dated 06 / 18 / 2021, page 112 / 238 The 108 / 198 reaction was filtered to remove inorganic solids and concentrated, resuspended in EA and washed with water. The organic layer is dried and concentrated, then purified by chromatography (MeOH / DCM) or preparative HPLC to provide the desired product. Alcohols protected by TBS were deprotected using 4N HCl. [000256] Compounds 17 to 20 and 91 to 95 were prepared using General Procedure 9. (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile [000257] Prepared using General Procedure 9. To a suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (50 mg, 0.12 mmol) in anhydrous DMF (5 mL) were added TEA (36.7 mg, 0.36 mmol) and (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol). The solution was stirred at 95°C. After 16 h more (2-bromoethoxy)(tert-butyl)dimethylsilane (34.6 mg, 0.14 mmol) was added and heating continued for 12 h. Water (5 mL) was added and the reaction mixture was extracted with EA (2 x 5 mL). The organic layers were washed with brine, dried, and purified by column chromatography (EA / hexanes) to provide 10 mg (15%) of (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile. The calculated LCMSESI (m / z) for: C29H38N4O2SSÍ: 534.3; obtained 535.3 [M+H]+, ír = 3.08 min. [000258] (S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile was prepared in an analogous manner using (S)-5-(5-(1-amino2,3-dihydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 4. Petition 870210054926, dated 06 / 18 / 2021, page 113 / 238 109 / 198 (R)-5-(5-(1 -((2-hydroxy ethyl)amino)-2,3-dihydro-1H-inden-4-yl)1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (Compound 17) [000259] To (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-I)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (10 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) were added 4N of HCl in dioxanes (0.5 mL). The mixture was stirred at room temperature for 3 hours and the solvent was evaporated. The crude material was purified by preparative HPLC to provide 7 mg (90%) of (R)-5-(5(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)2-isopropoxybenzonitrile 17.A LCMS-ESI (m / z) calculada para: C23H24N4O2S: 420,2; obteve 421.2 [M+H]+, fR= 2.38 min, 1H RMN (400 MHz, CDCI3) δ 8.19 (dd, J = 8.9, 2.3 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.88 (d, J = 7.7 Hz, 1H), 7.48 (t, J = 7.7 Hz, 1H), 7.10 (d, J = 9.0 Hz, 1H), 4.94 (d, J = 4.2 Hz, 1H), 4.76 (dt, J = 12.2, 6.1 Hz, 1H), 3.89 (d, J= 16.3 Hz, (2H), 3.68-3.20 (m, 2H), 3.20-2.89 (m, 2H), 2.72 - 2.53 (m, 2H), 2.65 - 2.53 (m, 1H), 2.49 - 2.27 (m, 1H), 1.44 (d, J= 6.1 Hz, 6H). 000260 -((2-((terc-butildimetilsilil)oxi)etiI)amino)-2,3di-hydro-1 Hi-conden-4-il )-1,3,4-tiadiazol-2-il) -2-isopropoxibenzonitrila. (S)-5-(5-(1-((2-((terc-butildimetilsilil) óxi)etil)amino)-2,3-dihidro-1H-inden-4-il)tiazol-2-il)-2-isopropoxibenzonitrila CN [000261] Prepared using General Procedure 9. To a suspension of (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4 hydrochloride Petition 870210054926, dated 06 / 18 / 2021, page 114 / 238 110 / 198 il)thiazol-5-yl)-2-isopropoxybenzonitrile 71 (25 mg, 0.06 mmol) in anhydrous DMF (2 mL) were added TEA (7.3 mg, 0.36 mmol) and (2-bromoethoxy-tert-butyl)dimethylsilane (6.9 mg, 0.14 mmol). The solution was stirred at 100°C for 48 hours. The reaction was diluted with EA (10 mL), washed with water and brine, and dried. Concentration and purification by column chromatography (EA / hexanes) yielded 29 mg (90%) of (S)5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-isopropoxybenzonitrile as a dark gray solid. LCMS-ESI (m / z) calculated for: C30H39N3O2SSÍ: 533.3; obtained 534.3 [M+H]+, fR = 3.22 min. [000262] (R)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-thiazol-2-yl)-2-isopropoxybenzonitrile was prepared analogously using (R)-5-(2-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 72. (S)-5-(5-(1-((2-Hydroxyethyl)amino)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-isopropoxybenzonitrile (Composto 92) [000263] To a solution of (S)-5-(5-(1-((2-((tert-butyldimethylsilyl)oxy)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2isopropoxybenzonitrile (10 mg, 0.018 mmol) in ether (1 mL) were added 2N HCl in ether (0.1 mL). The mixture was stirred at room temperature for 12 hours and the solvent was evaporated. The crude material was purified by preparative HPLC to provide 6 mg (80%) of (S)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1Hinden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 92. The LCMS-ESI (m / z) calculated for: C24H25N3O2S: 419.2; yielded 420.2 [M+H]+, fa = 2.43 min. [000264] (R)-5-(5-(1-((2-hydroxyethyl)amino)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-isopropoxybenzonitrile 91 was prepared analogously using (F?)-5-(5-(1-((2-((()erc-butyldimethyliso(I)i)oxyethyl)amino) Petition 870210054926, dated 06 / 18 / 2021, pp. 115 / 238 111 / 198 2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile. (S)-methyl 2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol2-yl)-2,3-di-hydro-1 H-inden-1 -yl)amino)acetate CN [000265] Prepared using General Procedure 9. To a suspension of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 4 hydrochloride (150 mg, 0.36 mmol) in CH3CN (5 mL) were added K2CO3 (150.9 mg, 1.09 mmol) and methyl 2-bromoacetate (67 mg, 0.43 mmol). The suspension was stirred at 80°C. After 6 h, more methyl 2-bromoacetate (6.7 mg, 0.043 mmol) was added and heating continued for 12 h. The reaction mixture was filtered and concentrated. The residue was resuspended in EA (15 mL), washed with water and brine, dried and concentrated. The product was purified by silica gel column chromatography (MeOH / DCM) to provide 146 mg (90%) of (S)-methyl 2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)amino)acetate as a white solid. LCMS-ESI (m / z) calculated for C24H24N4O3S: 448.2; obtained 449.1 [M+H]+, fR = 2.48 min. [000266] (R)-methyl 2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol 2-il)-2,3-di-hidro-1 H-inden-1-il)amino)acetato foi preparado de maneira análoga utilizando cloridrato de (R)-5-(5-(1-amino-2,3-di-hidro-1H inden-4-il)-1,3,4-tiadiazol-2-il)-2-isopropoxibenzonitrila 5. (S)-methyl 2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-di-hydro-1 H-inden-1 -yl)amino)acetate Petition 870210054926, 18 / 06 / 2021, pág. 116 / 238 112 / 198 [000267] To a solution of (S)-methyl 2-((4-(5-(3-cyano-4-isopropoxyphenyl)1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (146 mg, 0.35 mmol) in DCM (2 mL) was added di-tert-butyl dicarbonate (85.3 mg, 0.39 mmol) and the reaction was stirred at room temperature for 16 h. The reaction was diluted with DCM (10 mL) and washed with NaHCO3, water, and brine. The product was purified by silica gel column chromatography (EA / hexanes) to provide 118 mg (66%) of (S)-methyl 2-((tert-butoxycarbonyl)(4-(5(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden1-yl)amino)acetate as a white solid. The calculated LCMS-ESI (m / z) for C29H32N4O5S: 548.2; no M+ obtained, tr = 4.19 min. [000268] (R )-metil 2-(( terc-butoxicarbonyl)(4-(5-(3-ciano-4-isopropoxifenil)-1,3,4-thiadiazol-2-il)-2,3-di-hidro-1H-inden-1-il)amino)acetato foi preparado de maneira análoga utilizando (R)-metil 2-((4-(5-(3-ciano-4isopropoxifenil)-1,3,4-thiadiazol-2-il)-2,3-di-hidro-1H-inden-1il)amino)acetato. Ácido (S)-2-((terc-butoxicarbonyl)(4-( 5-( 3-cyano-4-isopropoxifenil)-1,3,4-thiadiazol-2-yl)-2,3-di-hidro-1H-inden-1-yl)amino)acético [000269] To a stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (120 mg, 0.21 mmol) in MeOH (2 mL) were added 6N sodium hydroxide solution (180 μL) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in water (5 mL) and acidified with 1N HCl. The mixture was extracted with EA (3 x 5 mL) and the organic layers washed with brine, dried over MgSO4, and concentrated to provide 108 mg (92%) of (S)-2-((tert-butoxycarbonyl) Petition 870210054926, dated 06 / 18 / 2021, pp. 117 / 238 113 / 198 butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3dihydro-1H-inden-1yl)amino)acetic acid as a white solid was used in subsequent experiments without purification. The LCMS-ESI (m / z) calculated for C28H30N4O5S: 534.2; no M+ obtained, tr = 3.81 min. 000270 terc butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3di-hidro-1H-inden-1-yl)amino)acetate. (S)-methyl 2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (Compound 99) [000271] Prepared using General Procedure 9. To a suspension of (S)-5-(2-(1-amino-2,3-dihydro-1H-inden-4yl)thiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 71 (150 mg, 0.36 mmol) in CH3CN (5 mL) were added K2CO3 (150.9 mg, 1.09 mmol) and methyl 2-bromoacetate (66 mg, 0.43 mmol). The suspension was stirred at 80°C for 16 h. The reaction mixture was filtered and concentrated. The residue was resuspended in EA (15 mL), washed with water and brine, dried and concentrated. The product was purified by silica gel column chromatography (EA / hexanes) to provide 76 mg (47%) of (S)-methyl 2-((4-(2-(3cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate as a white solid. The calculated LCMS-ESI (m / z) for C25H25N3O3S: 447.2; yielded 448.2 [M+H]+, tr = 2.57 min.1H RMN (400 MHz, CDCh) δ 8.23 ​​- 8.01 (m, 2H), 7.90 (s, 1H), 7.41 (dd, J = 21.0, 7.4 Hz, 1H), 7.29 (dd, J = 9.8, 5.2 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 7.04 (d, J = 8.9 Hz, 1H), 4.74 (dt, J = 12.1.6.1 Hz, 1H), 4.33 (t, J = 6.1 Hz, 1H), 3.76 (d, J = 4.8 Hz, 3H), 3.55 (s, 2H), 3.24 (ddd, J = 15,8, 8.2, 5.6 Hz, 1H), 3.05 - 2.86 (m, 1H), 2.47 - 2.25 (m, 2H), 2.02 - 1.84 (m, 1H), 1.53 - 1.36 (m, 6H),13C RMN (101. Petition: 870210054926, on 06 / 18 / 2021, page. 118 / 238 114 / 198 MHz, CDCb) δ 173.14, 164.87, 161.08, 146.06, 141.45, 141.28, 138.20, 132.13, 131.96, 128.08, 127.98, 127.56, 126.77, 124.66, 116.17, 114.01, 103.76, 72.55, 62.94, 52.19, 48.53, 32.99, 31.34, 22.04. 000272 (R)-5-(2-(1-amino-2,3-di-hydro-1H-inden-4il)tiazol-5-il)-2-isopropoxibenzonitrila 72. (S)-methyl 2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate Boc [000273] To a solution of (S)-methyl 2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate (76 mg, 0.17 mmol) in DCM (1 mL) di-tert-butyl dicarbonate (44.5 mg, 0.20 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction was diluted with DCM (10 mL) and washed with NaHCO3, water, brine and then dried. The filtrate concentration yielded 90 mg (96%) of (S)-methyl 2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate as a white solid. The calculated LCMS-ESI (m / z) for C30H33N3O5S: 547.21; no M+ obtained, ir = 4.42 min. [000274] (R)-metil 2-((terc-butoxicarbonyl)(4-(2-(3-ciano-4-isopropoxifenil) tiazol-5-il)-2,3-di-hidro-1 H-inden-1-il)amino)acetato foi preparado de maneira análoga utilizando (R)-metila 2-((4-(5-(3-ciano-4-isopropoxyfeni I)-1,3,4-tiad iazol-2-i I )-2,3-di-hidro-1 H-inden-1 -il) amino) acetato. Ácido (S)-2-((terc-butoxicarbonyl)(4-(2-(3-cyano-4-isopropoxifenil) tiazol-5-yl)-2,3-di-hidro-1 H-inden-1 -yl)amino)acético Petition 870210054926, 18 / 06 / 2021, pág. 119 / 238 115 / 198 [000275] To a stirred solution of (S)-methyl 2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino) acetate (120 mg, 0.22 mmol) in MeOH (2 mL) were added 6N sodium hydroxide (180 μL) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was dissolved in water (5 mL) and acidified with 1N HCl. The mixture was extracted with EA (3 x 5 mL) and the organic layers washed with brine, dried over MgSO4, and concentrated to provide 110 mg (94%) of (S)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1yl)amino)acetic acid as a white solid that was used in subsequent experiments without purification. The calculated LCMS-ESI (m / z) for C29H31N3O5S: 533.2; yielded 534.2 [M+H]+, tr = 3.92 min. [000276] (R)-2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid was prepared analogously using (R)-methyl 2-((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate. General Procedure 10. Preparation of Indano Amino Amides [000277] To the Boc-protected amino acid (R)- or (S)-indane (1 equivalent) in DMF (2 M) were added HOBt (1.35 eq) and EDC (1.35 eq) and the reaction was stirred at room temperature for 60 min. The appropriate amine (1.1 eq) was added and the reaction was stirred at room temperature for 2 h. The Boc-protected amino amide was precipitated out of water or extracted with EA and dried over MgSO4. The product was purified by recrystallization or preparative HPLC. The resulting solid was heated in 4M HCl / dioxane at 50°C until the reaction was complete. The product was precipitated as a hydrochloride salt by the addition of diethyl ether. [000278] Compounds 21 to 25, 39, and 98, 100 to 108 were Petition 870210054926, dated 06 / 18 / 2021, pp. 120 / 238 116 / 198 prepared using General Procedure 10. (S)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamide hydrochloride (Compound 21) [000279] Prepared using General Procedure 10. (S)2-((tert-butoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)amino)acetic acid (25 mg, 0.04 mmol) was added to HOBt (9.4 mg, 0.07 mmol) and EDC (13.3 mg, 0.07 mmol) in anhydrous DMF (1 mL) and the reaction mixture was stirred at room temperature for 60 min. Dimethylamine (2.3 mg, 0.05 mmol) was added and the mixture was stirred at room temperature for 12 h. The crude reaction was purified by preparative HPLC purification to provide the Boc-protected amide as the white solid. This material was treated with 4N HCl in dioxane at 50°C for 2 h. The reaction mixture was diluted with diethyl ether (5 mL), and the resulting solid was collected to provide 10 mg (46% in two steps) of (S)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamide hydrochloride 21.LCMS-ESI (m / z) calculated for C25H27N5O2S: 461.2; obtained 462.1 [M+H]+, fR= 3.90 min. [000280] (F?)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)-N,N-dimethylacetamide 22 hydrochloride was prepared in a similar way using acid (R)-2-((tertbutoxycarbonyl)(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3dihydro-1H-inden-1yl)amino)acetic acid. 5-(5-((S)-1-((2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile Petition 870210054926, dated 06 / 18 / 2021, pages 121 / 238 117 / 198 (Compound 104) [000281] Prepared using General Procedure 10. (S)-2((tert-butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid (12 mg, 0.02 mmol) and HOBt (4.5 mg, 0.03 mmol) were added to EDC (6.4 mg, 0.03 mmol) in anhydrous DMF (1 mL) and the reaction mixture was stirred at room temperature for 60 min. (S)-pyrrolidin-3-ol (2.3 mg, 0.02 mmol) was added and the mixture was stirred at room temperature for 12 h. The crude reaction was purified by preparative HPLC purification to provide the Boc-protected amide as the white solid. This material was treated with 4N HCl in dioxane at 50°C for 2 h. The reaction mixture was diluted with diethyl ether (5 mL), and the resulting solid was collected to provide 5 mg (50% in two steps) of 5-(5-((S)-1((2-((S)-3-hydroxypyrrolidin-1-yl)-2-oxoethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 104.The LCMS-ESI (m / z) calculated for C28H30N4O3S: 502.2; obtained 503.2 [M+H]+, tr = 3.77 min. [000282] 5-(5-(( R )-1-((2-(( S )-3-hydroxypyrrolidin-1-yl)-2oxoethyl) amino)-2,3-dihydro-1 H-inden-4-yl) thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 102 was prepared in an analogous manner using acid (R )-2-(( tert -butoxycarbonyl)(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5yl)-2,3-dihydro-1H-inden-1-yl)amino) acetic. (R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid (Compound 27) [000283] To a stirred solution of (R)-2-((tert-butoxycarbonyl)(4) acid. Petition 870210054926, dated 06 / 18 / 2021, page 122 / 238 118 / 198 (5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid (20 mg, 0.03) mmol in 1,4-dioxane (0.5 mL) were added 4N HCl in 1,4-dioxane (0.2 mL). The mixture was stirred at 50°C for 2 h before being concentrated and triturated with ether to provide 13 mg of (R)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid as a yellowish-green solid. LCMS-ESI (m / z) calculated for C23H22N4O3S: 434.14, obtained 435.2 [M+H]+, tR= 2.51 min. [000284] (S)-2-((4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid 26 was prepared in a similar manner using (S)-2-((tert-butoxycarbonyl)(4-(5-(3cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid. (R)-2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3dihydro-1H-inden-1-yl)amino)acetic acid (Compound 96) [000285] (R)-methyl 2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)2,3-dihydro-1H-inden-1-yl)amino)acetate (100 mg, 0.22 mmol) in ethanol were added 2N NaOH (1.1 mL) and the mixture was stirred at room temperature for 12 h. The solvent was evaporated and the residue dissolved in water and acidified with 1N HCl. The resulting solid was filtered and dried to give 60 mg (63%) of (R)2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetic acid as a yellowish-green solid. LCMS-ESI (m / z) calculated for C24H23N3O3S: 433.1; obtained 434.2 [M+1] ]+, tR= 2.61 min. [000286] (S)-2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)2,3-dihydro-1H-inden-1-yl)amino)acetic acid 97 was prepared in a manner Petition 870210054926, dated 06 / 18 / 2021, pages 123 / 238 119 / 198 analog using (S )-methyl 2-((4-(2-(3-cyano-4-isopropoxyphenyl)thiazol5-yl)-2,3-dihydro-1H-inden-1-yl)amino)acetate. General Procedure 11. Indanoamine Reduction Aminations. [000287] To a solution of optionally substituted primary or secondary (R)- or (S)-indane amine (1 eq) in MeOH (0.01 M) were added acetic acid (0.01 eq) and the appropriate aldehyde (1.1 eq). The reaction was stirred at 25-50°C until imine formation was complete (2-18 h). Sodium borohydride or sodium triacetoxyborohydride (10 eq) was added and the reaction was stirred at room temperature until reduction was complete (2-8 h). The solvent was evaporated and the residue partitioned between NaHCO3 and EA. The organic layer was collected, dried, and purified by preparative HPLC. [000288] Compounds 28 to 30, 109 and 110 were prepared using General Procedure 11. (S)-5-(5-(1-(((1H-imidazol-2-yl)methyl)amino)-2,3-dihydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile (Compound 28) [000289] Prepared using General Procedure 11. Acetic acid (1 drop) was added to (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (25 mg, 0.06 mmol) and 1H-imidazole-2-carbaldehyde (6.4 mg, 0.06 mmol) in anhydrous MeOH (1 mL). The solution was stirred at 55°C for 3 h before cooling to room temperature and adding NaBH4 (4.6 mg, 0.12 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was rapidly cooled with water (0.5 mL) and divided between EA (5 mL) and water (5 mL). The organic layers are washed with water and brine, and the product is purified by preparative HPLC to provide 22 mg. Petition 870210054926, dated 06 / 18 / 2021, pages 124 / 238 120 / 198 (81%) of (S)-5-(5-(1-(((1 H-imidazol-2-yl)methyl)amino)-2,3-di-hydro1 H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 28 as a solid branch. A LCMS-ESI (m / z) calculated for C25H24N6OS: 456.2; obtained 457.2 [M+H]+, fR= 2.38 min. [000290] (R)-5-(5-(1-(((1 H-imidazol-2-yl)methyl)amino)-2,3-dihydro1H-inden-4-yl)-1,3,4-thiadiazol-2-yl) -2-isopropoxybenzonitrile 29 was prepared by anhydrogenic anhydrate (R)-5-(5-(1amino-2,3-di-hydro-1 Hi nden-4-i I)-1,3,4-thiadiazol-2-yl )-2isopropoxybenzonitrile 5 . (R)-5-(5-( 1-((( 1H-imidazol-2-yl)methyl)amino)-2,3-di-hydro1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile (Compound 109) [000291] Prepared using General Procedure 11. (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 72 (20 mg, 0.05 mmol) and 1 / - / -imidazol-2-carbaldehyde (7 mg, 0.07 mmol) in anhydrous MeOH (0.5 mL) was added to acetic acid (1 drop). The solution was stirred at 55°C for 3 h before cooling to room temperature and adding NaBH4 (37.8 mg, 0.1 mmol). The mixture was stirred at room temperature for 12 h. The reaction mixture was rapidly cooled with water (0.5 mL) and divided between EA (5 mL) and water (5 mL). The organic layers were washed with water and brine, and the product purified by preparative HPLC to provide 17 mg (77%) of (R)-5-(5-(1-(((1H-imidazol-2yl)methyla)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 109. The LCMS-ESI (m / z) calculated for C26H25N5OS: 455.2; obtained 456.2 [M+H]+, fR= 2.53 min. [000292] (S)-5-(5-(1 -(((1 H-imidazol-2-yl)methyla)amino)-2,3-di-hidro-1 Hinden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrila 110 foi preparada de Petition 870210054926, 18 / 06 / 2021, pág. 125 / 238 121 / 198 maneira análoga utilizando cloridrato de (S)-5-(5-(1-amino-2,3-di-hidro1 H-inden-4-il) tiazol-2-il)-2-isopropoxibenzonitrila 71. (S)-2-isopropoxy-5-( 5-(1-((2-(methylsulfonyl) ethyl)amino)-2,3di-hydro-1 H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile (Compound 31) [000293] To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (25 mg, 0.06 mmol) and DIEA (32 mg, 0.24 mmol) in DMA (1 mL) (methylsulfonyl)ethene (20 mg, 0.18 mmol) was added. The reaction mixture was heated at 90°C for 24 h. The solvent was evaporated and the product purified by preparative HPLC to provide 9 mg (31%) of (S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile 31 as a half-white solid. The calculated LCMS-ESI (m / z) for C24H26N4O3S2: 482.1; yielded 483.1 [M+H]+, fR = 2.49 min. [000294] (R)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)benzonitrile 32 was prepared in an analogous manner using hydrochloride (R)-5-(5-(1-amino-2,3-dihydro1H-inden-4-iI)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 5. (S)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)benzonitrile (Compound 221) [000295] To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 71 hydrochloride (60 mg, 0.15 mmol) and DIEA (32 mg, 0.24 mmol) in 1,4-dioxane (0.5 mL) was added (methylsulfonyl)ethene (92 mg, 0.88 mmol). The reaction mixture was heated at 90°C for 24 h. The reaction was diluted with DCM. Petition 870210054926, dated 06 / 18 / 2021, pages 126 / 238 122 / 198 (5 mL) and washed with saturated aqueous ammonium chloride (2 x 5 mL) and saturated aqueous sodium bicarbonate (2 x 5 mL) and then dried. The crude reaction was purified by a silica gel column (MeOH / DCM) to yield 44 mg (61%) of (S)-2-isopropoxy-5-(5-(1-((2(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2yl)benzonitrile 221 as a brown liquid. The LCMS-ESI (m / z) calculated for C25H27N3O3S2: 481.1; obtained 482.1 [M+H]+, r = 2.49 min, 1H NMR (400 MHz, CDCl3) δ 8.19-8.08 (m, 2H), 7.92 (s, 1H), 7.46 (dd, J = 7.4, 0.9 Hz, 1H), 7.33 (dt, J = 14.9, 7.3 Hz, 2H), 7.06 (d, J = 8.9 Hz, 1H), 5.31 (s, 1H), 4.75 (dt, J= 12.2,6.1 Hz, 1H), 4.35 (t, J = 6.6 Hz, 1H), 3.41 -3.15 (m, 5H), 3.10-2.96 (m, 4H), 2.57-2.45 (m, 1H), 1.93 (ddd, J = 12.8, 6.2, 1.7 Hz, 1H), 1.46 (d, J = 6.1 Hz, 6H). [000296] (R)-2-isopropoxy-5-(5-(1-((2-(methylsulfonyl)ethyl)amino)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)benzonitrile 220 was prepared in an analogous manner using hydrochloride (R)-5-(5-(1-amino-2,3-dihydro-1Hinden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 72. General Procedure 12. Preparation of Indane Sulfonamides from Sulfonyl Chlorides [000297] To a stirred solution of (R)- or (S)-indanoamine (1 eq) in DCM (0.08M) were added TEA (3 eq) and the appropriate sulfonyl chloride (1.5 eq.) at room temperature. The reaction was stirred at room temperature for 18 h. The solvent was evaporated and the pure product isolated after purification with preparative HPLC. [000298] Compounds 33 to 36 and 111 to 120 were prepared using General Procedure 12. (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)methanesulfonamide (Compound 33) Petition 870210054926, dated 06 / 18 / 2021, pages 127 / 238 123 / 198 [000299] Prepared using General Procedure 12. To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (20 mg, 0.04 mmol) and TEA (14.7 mg, 0.4 mmol) in DCM (2 mL) methane sulfonylchloride (8.3 mg, 0.07 mmol) was added and the mixture was stirred at room temperature for 16 h. The solvent was evaporated and the residue purified by preparative HPLC to provide 12 mg (55%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide 33 as a white solid. The calculated LCMS-ESI (m / z) for C22H22N4O3S2: 454.1; yielded 455.1 [M+H]+, tr = 3.48 min. [000300] (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)methanesulfonamide 34 was prepared in an analogous manner using (R)-5- hydrochloride (5-(1-amino-2,3-dihydro1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 5. (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide (Compound 111) Isopropoxybenzonitrile 72 (60 mg, 0.15 mmol) and TEA (0.06 mL, 0.4 mmol) in DCM (0.5 mL) were added to methanesulfonylchloride (8.3 mg, 0.07 mmol) at 0°C and the reaction mixture was stirred at room temperature for 16 h. The mixture was diluted with DCM (5 mL) and washed with aqueous ammonium chloride and brine. The crude material was purified by silica gel column chromatography (MeOH / DCM) to provide 39 mg (58%) of (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide 111 as a white solid. Petition 870210054926, of 18 / 06 / 2021, p. 128 / 238 124 / 198 LCMS-ESI (m / z) calculated for C23H23N3O3S2: 453.1; obtained 454.1 [M+H]+, fa = 3.64 min. [000302] (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1 H-inden-1-yl)methanosulfonamide 112 was similarly prepared using hydrochloride of (S)-5-(5-(1-amino-2,3-di-hydro-1Hinden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 71. (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-di-h hydro-1 H-in den-1-yl)ethene osulfonamide CN [000303] To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (40 mg, 0.5 mmol) and TEA (49 mg, 0.48 mmol) in DCM (2 mL) 2-chloroethanesulfonyl chloride (79 mg, 0.48 mmol) was added at 0°C. The reaction was heated at room temperature and stirred for 2 h. The reaction was rapidly cooled by the addition of NaHCO3. The product was purified by chromatography (EA / hexane) to provide 30 mg (66%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide as a yellow solid. The calculated LCMS-ESI (m / z) for C23H22N4O3S2: 466.1; yielded 467.1 [M+H]+, fa = 3.63 min. [000304] (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)ethenesulfonamide was prepared in an analogous manner using hydrochloride (R)-5-(5-(1-amino-2,3-dihydro-1Hinden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile 5. (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide CN Petition 870210054926, dated 06 / 18 / 2021, pp. 129 / 238 125 / 198 [000305] (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 72 (0.5 g, 1.3 mmol) in DCM (10 mL) was added TEA (0.88 mL, 6.3 mmol) followed by 2-chloroethanesulfonyl chloride (0.4 mL, 163 mmol) at 0°C and the reaction was stirred at room temperature overnight. During this time, additional reagents TEA (0.2 mL) and 2-chloroethanesulfonyl chloride (0.15 mL) were added to drive the reaction to completion. The reaction mixture was concentrated and the crude residue was purified by a silica gel column (EA / hexanes) to provide 378 mg of (R)-N-(4-(2-(3cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1yl)ethenesulfonamide as a fine yellow powder. The calculated LCMS-ESI (m / z) for C24H23N3O3S2: 465.12; yielded 466.1 [M+H]+, tr = 3.82 min.1H NMR (400 MHz, CDCh) δ 8.10 (s, 2H), 7.85 (s, 1H), 7.48 - 7.26 (m, 3H), 7.01 (d, J = 7.3 Hz, 1H), 6.64 (dd, J = 16.5, 9.8 Hz, 1H), 6.33 (d, J = 16.5 Hz, 1H), 5.97 (d, J = 9.8 Hz, 1H), 4.90 (d, J = 7.3 Hz, 1H), 4.77 - 4.46 (m, 2H), 3.32 - 2.83 (m, 2H), 2.64 (s, 1H), 2.02 - 1.84 (m, 1H), 1.40 (t, J = 5.8 Hz, 6H). [000306] (S )-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl) ethanesulfonamide was prepared in an analogous manner using (S)-5-(5-(1-amino-2,3-dihydro-1Hinden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 71. General Procedure 13. Preparation of Indane Sulfonamides via Michael Addition [000307] To a stirred solution of (R)- or (S)-indane vinyl sulfonamide (1 eq) in DMF (0.1M) the appropriate amine (10 eq) was added. The reaction was stirred at 80°C for 18 h. The product was purified by preparative HPLC. [000308] Compounds 37 to 38 and 121 to 153 were prepared using General Procedure 13. N-((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl) Petition 870210054926, dated 06 / 18 / 2021, page 130 / 238 126 / 198 2,3-dihydro-1H-inden-1-yl)-2-((R)-3-h hydroxypyrrolidin-1yl)ethanesulfonamide (Compound 37) [000309] Prepared using General Procedure 13. To a solution of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)ethenesulfonamide (40 mg, 0.5 mmol) in DMF (0.5 mL) (R)-pyrrolidin-3-ol (18.7 mg, 0.21 mmol) was added and the reaction was heated at 80°C for 18 h. The product was purified by preparative HPLC to give 30 mg (56%) of N-((S)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide 37 as a whitish solid. The LCMS-ESI (m / z) calculated for C27H31N5O4S2: 553.2; yielded 554.2 [M+H]+, tr = 2.52 min. [000310] N-((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypyrrolidin-1-yl)ethanesulfonamide 38 was prepared in an analogous manner using (R)-N-(4-(5-(3-cyano-4isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1yl)ethenesulfonamide. N-((R)-4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide (Compound 143) [000311] Prepared using General Procedure 13. To a solution of (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide (10 mg, 0.2 mmol) in DMF (0.5 mL) was added (R)-piperidin-3-ol hydrochloride (20.6 mg, 0.15 mL) Petition 870210054926, dated 06 / 18 / 2021, pages 131 / 238 127 / 198 mmol) and the reaction was heated at 80°C for 18 h. The product was purified by preparative HPLC to give 10 mg (80%) of N-((R)4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide 143. The calculated LCMS-ESI (m / z) for C29H34N4O4S2: 566.2; obtained 567.2 [M+H]+, tr = 2.62 min. [000312] N-((S)-4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-((R)-3-hydroxypiperidin-1-yl)ethanesulfonamide 141 was prepared analogously using (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)ethenesulfonamide. General Procedure 14. Preparation of Indano Sulfonamide Esters [000313] To a stirred solution of (R)- or (S)-indanoamine (1 eq) in DCM (0.2 M) sulfonyl chloride (1.5 eq) was added at room temperature. Less reactive or hindered sulfonyl chloride esters were added to DIEA (2-3 eq). The reaction was stirred at room temperature for 18 h. The crude reaction was split between DCM and NaHCO3. The organic layer was dried over MgSO4, concentrated, and purified by column chromatography. [000314] Compounds 154 to 157 were prepared using General Procedure 14. (S)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate [000315] Prepared using General Procedure 14: To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2yl)-2-isopropoxybenzonitrile 4 (177 g, 0.47 mmol) and DIEA (182 mg, 1.4 mmol) in DCM (8 mL) was added freshly prepared ethyl-2-(chlorosulfonyl)acetate (131 mg, 0.7 mmol). After 45 min, the crude reaction was split between DCM and NaHCOa. The organic layer was dried over MgSO4. Petition 870210054926, dated 06 / 18 / 2021, pages 132 / 238 128 / 198 concentrated, and purified by column chromatography (EA / hexanos) to provide 75 mg (30%) of (S)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)1,3,4-thiadiazol-2-yl)-2,3-di-hidro-1H-inden-1-yl)sulfamoyl)acetate as an amarelo-claro solid. A LCMS-ESI (m / z) calculated for C25H26N4O5S2: 526.1; obteve 527.1 [M+H]+, tr = 3.71 min,1H NMR (400 MHz, CDCh) δ 8.16 (dd, J = 8.9, 2.3 Hz, 1H), 8.09 (d, J = 2.2 Hz, 1H), 7.76 (d, J = 7.7 Hz, 1H), 7.57 (d, J = 7.6 Hz, 1H), 7.35 (t, J = 7.6 Hz, 1H), 7.03 (d, J = 9.0 Hz, 1H), 5.46 (t, J = 7.9 Hz, 1H), 4.70 (dt, J = 12.2, 6.1 Hz, 1H), 4.26 - 4.17 (m, 2H), 4.00 (d, J = 8.2 Hz, 2H), 3.49 (ddd, J = 17.4, 9.5, 3.9 Hz, 1H), 3.26 3.05 (m, 1H), 2.56 (ddd, J = 12.9, 9.0, 4.4 Hz, 1H), 2.23 - 2.08 (m, 1H), 1.41 - 1.37 (m, 6H), 1.28 (dd, J = 11.7, 4.6 Hz, 3H). [000316] (R )-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxifenil)-1,3,4-thiadiazol2-il)-2,3-di-hidro-1H-inden-1-il)sulfamoil)acetato foi preparado de maneira análoga utilizando (R)-5-(5-(1-amino-2,3-di-hidro-1H-inden-4il)-1,3,4-thiadiazol-2-il)-2-isopropoxibenzonitrila 5. (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (Compound 155) [000317] Prepared using General Procedure 14: To a solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 71 (20 mg, 0.04 mmol) in DCM (1 mL) was added methyl-2-(chlorosulfonyl)acetate (10 mg, 0.04 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with DCM (5 mL), washed with saturated aqueous NaHCOa, and brine. The organic layers were dried over MgSO4, and the crude product purified by silica gel column chromatography to provide 11.2 mg (41%) of (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate Petition 870210054926, dated 06 / 18 / 2021, pages 133 / 238 129 / 198 155 as a brownish-orange oil. The LCMS-ESI (m / z) calculated for C25H25N3O5S2: 511.1; obtained 512.2 [M+H]+, ír = 3.71 min. [000318] (R)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3dihydro-1H-inden-1-yl)sulfamoyl)acetate 154 was prepared in an analogous manner using (R)-5-(5-(1-amino-2,3-dihydro-1 H-inden-4-yl)thiazol-2yl)-2-isopropoxybenzonitrile 72. General Procedure 15. Preparation of Indane Sulfonamide Acids [000319] To a solution of (R)- or (S)-indane sulfonamide ester (1 eq) in 2:1 EtOH / THF (0.2 M) were added 6N of NaOH (5 eq) at room temperature. The reaction was stirred at room temperature for 24 h. The crude reaction was concentrated and then split between DCM / IPA and 1N HCl. The organic layer was dried over MgSO4, concentrated, and isolated after purification with preparative HPLC. [000320] Compounds 40 to 41 and 158 to 161 were prepared using General Procedure 15. (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid (Compound 40) [000321] Prepared using General Procedure 15. To a stirred solution of (S)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl) acetate (75 mg, 0.8 mmol) in MeOH (4 mL) were added 6N NaOH (0.12 mL). After 3 h, the crude reaction was concentrated and then divided between DCM / IPA and 1N HCl. The organic layer was dried over MgSO4 and concentrated to give 43 mg (60%) of (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 40 as a light yellow solid. The LCMS-ESI (m / z) calculated for C23H22N4O5S2: 498.1; yielded 499.1 [M+H]+, fa = 3.34 min. Petition 870210054926, dated 06 / 18 / 2021, pages 134 / 238 130 / 198 [000322] (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 41 was prepared analogously using (R)-ethyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate. (S)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid (Compound 159) [000323] Prepared using General Procedure 15 To a stirred solution containing (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (11.2 mg, 0.02 mmol) in MeOH (1 mL) were added 6N NaOH (100 µL). After 1 h, the crude reaction was concentrated and the product purified by preparative HPLC to give 5 mg (45%) of (S)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid as a pale yellow solid. LCMS-ESI (m / z) calculated for C24H23N3O5S2: 497.1; obtained 498.1 [M+H]+, tR= 3.44 min. [000324] (R)-2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetic acid 158 was prepared analogously using (R)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate. General Procedure 16. Preparation of Indane Sulfonamide Amides [000325] To a stirred solution of (R)- or (S)-indane sulfonamide acid (1 eq) in DCM (0.25 M) were added HATU (3 eq) and DIEA (2 eq). After 30 min, the amine was added and the reaction mixture stirred for 18 h at room temperature. The reaction was rapidly cooled with water and purified by preparative HPLC. [000326] Compounds 42 to 44, 162, and 163 were prepared using General Procedure 16. Petition 870210054926, dated 06 / 18 / 2021, pages 135 / 238 131 / 198 (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2H)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide (Compound 43) [000327] Prepared using General Procedure 1&. To (R)2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1Hinden-1-yl)sulfamoyl)acetic acid (20 mg, 0.04 mmol) in DCM (0.4 mL) were added HATU (45 mg, 0.12 mmol) and DIEA (10.3 mg, 0.08 mmol). After 30 min, dimethylamine (2M solution in THF, 200 pL, 0.4 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was rapidly cooled with water (100 pL) and the solvent evaporated. The crude material was purified by preparative HPLC to provide 14 mg (66%) of (R)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)-N,N-dimethylacetamide 43 as a white solid.A LCMS-ESI (m / z) calculada para C25H27N5O4S2: 525,2; obteve 526,2 [M+H]+, ír = 3,42 min,1H RMN (400 MHz, CDCI3) δ 8,20 (dd, J = 8,9, 2,3 Hz, 1H), 8,14 (d, J = 2,3 Hz, 1H), 7,82 (d, J= 7,7 Hz, 1H), 7,73 (d, J= 7,6 Hz, 1H), 7,40 (t, J = 7,7 Hz, 1H), 7,09 (d, J = 9,0 Hz, 1H), 5,50 (d, J = 8,2 Hz, 1H), 5,07 (q, J = 7,7 Hz, 1H), 4,76 (hept, J= 6,1 Hz, 1H), 4,28 (d, J = 14,6 Hz, 1H), 4,09 (d, J = 14,6 Hz, 1H), 3,50 (ddd, J = 17,0, 8,8, 3,4 Hz, 1H), 3,20 (dt, J = 9,7, 7,1 Hz, 1H), 3,15 (s, 3H), 3,02 (s, 3H), 2,72 (dtd, J = 11,4, 8,0, 3,5 Hz, 1H), 2,20 (dq, J= 13,1,8,4 Hz, 1H), 1,46 (d, 6,1 Hz, 6H),13C RMN (101 MHz, CDCI3) δ 166,99, 165,73, 163,22, 161,71, 144,17, 141,92, 133,44, 133,34, 129,31, 127,92, 127,33, 126,37, 122,70, 115,57, 113,91, 103,71, 72,56, 59,23, 54,92, 38,30, 35,99, 31,36, 21,74, HPLC Quiral: (R)-2-(N-(4-(5-(3-ciano-4-isopropoxifenil)-1,3,4-tiadiazol-2-il)-2,3-dihidro-1H-inden-1-il)sulfamoil)-N,N-dimetilacetamidafoi eluída em 40% de IPA em hexanos, 100% ee, ír = 22,87 min. Petition 870210054926, dated 06 / 18 / 2021, p. 136 / 238 132 / 198 [000328] (S)-2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl) -2,3-di-hydro-1 H-inden-1 -yl)sulfamoyl)-N,N-dimethyl acetamide prepared mannethylacetamide agon 42 (S)-2-(N-(4-(5-(3-cyano4-isopropoxyphenyl)-1,3,4-ti adi azol-2-i I )-2,3-di-hyd ro-1 H-inden-1 -yl) sulfamoyl) acetic acid. Chiral HPLC: 97.8 % ee, go to S-enantiomer = 29.06 min. (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-di-hydro1 H-inden-1 -yl)-2-morpholino-2-oxoethanosulfonamide (Compound 162) [000329] Prepared using General Procedure 16'. To (R)2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1yl)sulfamoyl)acetic acid 158 (15 mg, 0.03 mmol) in DCM (0.4 mL) were added HATU (26 mg, 0.07 mmol) and DIEA (7.8 mg, 0.06 mmol). After 30 min, morpholine (52 mg, 0.6 mmol) was added and the reaction stirred for 18 h at room temperature. The reaction was rapidly cooled with water (100 µL) and the solvent evaporated. The crude material was purified by preparative HPLC to provide 8 mg (47%) of (F?)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1Hinden-1-yl)-2-morpholino-2-oxoethanesulfonamide 162. The calculated LCMS-ESI (m / z) for C28H30N4O5S2: 566.1; yielded 567.2 [M+H]+, r = 3.77 min. General Procedure 17. Preparation of Indane Sulfonamide Alcohols [000330] To a stirred solution of (R)- or (S)-indane sulfonamide ester (1 eq) in THF (0.06 M) sodium borohydride (4 eq) was added at room temperature.The reaction was heated to 75°C and methanol (10 eq) was added dropwise. After 1 h, the reaction was cooled and concentrated. The pure product was obtained by purification with preparative HPLC. [000331] Compounds 45, 46, 164, and 165 were prepared using General Procedure 17. Petition 870210054926, dated 06 / 18 / 2021, pages 137 / 238 133 / 198 (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide (Compound 46) [000332] Prepared using General Procedure 17 To a stirred solution of (R)-methyl 2-(N-(4-(5-(3-cyano-4-isopropoxyphenyl)1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl) acetate (13 mg, 0.02 mmol) in THF (0.5 mL) sodium borohydride (2.3 mg, 0.06 mmol) was added at room temperature. The reaction was heated to 75°C and methanol (0.03 mL, 0.7 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. Purification of the crude material by preparative HPLC yielded 6 mg (60%) of (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 46.A LCMS-ESI (m / z) calculated for C23H24N4O4S2: 484.1; obteve 485.1 [M+H]+, fa = 3.26 min,1H NMR (400 MHz, CDCI3) δ 8.23 ​​(dd, J = 8.9, 2.3 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.64 (d, J = 7.6 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.11 (d, J= 9.0 Hz, 1H), 5.19-4.96 (m, 1H), 4.87-4.63 (m, 3H), 4.17 (dd, J = 8.2, 4.4 Hz, 2H), 3.53 (ddd, J = 17.2, 8.8, 3.5 Hz, 1H), 3.46 3.34 (m, 2H), 3.32-3.11 (m, 1H), 2.86-2.59 (m, 1H), 2.19-1.97 (m, 1H), 1.48 (d, J = 6.1 Hz, 6H),13C NMR (101 MHz, CDCI3) δ 166.83, 165.72, 161.71, 144.11, 141.85, 133.47, 133.26, 129.53, 127.99, 126.92, 126.58, 122.64, 115.51, 113.87, 103.79, 72.54, 58.86, 57.43, 55.67, 34.69, 31.27, 21.73, HPLC Quiral: (R)-N-(4-(5-(3-cyano-4isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-di-hidro-1 H-inden-1 -yl)-2hidroxietanosulfonamida foi eluída in MeOH, 96.2% ee, fa = 12.58 min (Quiral Method 2). [000333] (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 45 was prepared analogously using (S)-methyl 2-(N-(4-(5-(3-cyano-4-Isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 45 Petition 870210054926, dated 06 / 18 / 2021, page 138 / 238 134 / 198 isopropoxyphenyl)-1,3,4-thiadiazol-2-yl) -2,3-dihydro-1H-inden-1-yl) sulfamoyl) acetate. Chiral HPLC: 97.6% ee, tr for S-enantiomer = 10.99 min (Chiral Method 2). (S)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide (Compound 165) [000334] Prepared using General Procedure 17: To a stirred solution of (S)-methyl 2-(N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate (20 mg, 0.04 mmol) in THF (0.5 mL) was added sodium borohydride (3.6 mg, 0.09 mmol) at room temperature. The reaction was heated to 75°C and methanol (0.06 mL, 1.4 mmol) was added dropwise. After 1 h, the reaction was cooled and concentrated. Purification of the crude material by preparative HPLC yielded 12.2 mg (64%) of (S)-N-(4-(2-(3cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 165. The calculated LCMS-ESI (m / z) for C24H25N3O4S2: 483.1; obtained 484.2 [M+H]+, tr = 3.45 min. [000335] (R )-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)-2-hydroxyethanesulfonamide 164 was prepared in an analogous manner using (R )-methyl 2-(N-(4-(2-(3-cyano-4isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamoyl)acetate. General Procedure 18. Preparation of Indane Sulfonamides [000336] To a stirred solution of (R)- or (S)-indaneamine (1 eq) in 1,4-dioxane (0.06M) sulfonamide (5 eq) was added and the reaction was stirred at 90°C for 16 h. The solvent was evaporated and the reaction mixture was purified by preparative HPLC. [000337] Compounds 47, 48, 166, and 167 were prepared using General Procedure 18. (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl) Petition 870210054926, dated 06 / 18 / 2021, page 139 / 238 135 / 198 2,3-dihydro-1H-inden-1-yl)sulfamide (Compound 47) [000338] Prepared using General Procedure 18: (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (25 mg, 0.06 mmol) in dioxane (1 mL) was added sulfonamide (30 mg, 0.3 mmol) and the mixture was heated to 90°C. After 16 h, the solvent was evaporated and the residue was purified by column chromatography. Further purification by recrystallization of MeOH yielded 15.9 mg (26%) of (S)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl) sulfonamide 47.The LCMS-ESI (m / z) calculated for C21H21N5O3S2: 455.1; obtained 456.1 [M+H]+, tr = 3.33 min,1H NMR (400 MHz, DMSO) δ 8.40 (d, J = 2.3 Hz, 1H), 8.32 (dd, J = 8.9, 2.4 Hz, J71, 17 (H), 7.7 7.66 (d, J = 7.6 Hz, 1H), 7.56 - 7.38 (m, 2H), 7.23 (d, J = 9.0 Hz, 1H), 6.75 (s, 2H), 4.95 (dt, J = 11.6, J = 67.1), Hz 8.2 Hz, 1H), 3.42 – 3.26 (m, 1H), 3.07 (dt, J = 16.4, 8.3 Hz, 1H), 2.61 (dtd, J = 11.0, 7.9, 3.0 Hz, 1H (8, 2.7), q 2.0 1H), 1.38 (d, J = 6.0 Hz, 6H),13C NMR (101 MHz, DMSO) δ 166.64, 165.62, 161.19, 146.08, 141.36, 133.12.815, 13.13. HPLC Chiral: (S )-N(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-di-hydro-1Hinden-1-yl)sulfamide was eluted in MeOH: 98.6% ee, tr = 7.63 min (Chiral Method 2). [000339] (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)2,3-dihydro-1H-inden-1-yl) sulfonamide 48 was prepared analogously using (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride. Chiral HPLC: 98% ee, tr for R-enantiomer = 9.10 min (Chiral Method 2). Petition 870210054926, dated 06 / 18 / 2021, pages 140 / 238 136 / 198 (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide (Compound 166) [000340] Prepared using General Procedure 18: (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 72 (100 mg, 0.02 mmol) in dioxane (1 mL) were added DIEA (58 mg, 0.32 mmol) and sulfonamide (115 mg, 1.2 mmol) and the reaction was heated at 90°C for 4 h. The solvent was evaporated and the residue was diluted with EA (10 mL) and successively washed with NH4Cl and brine. The product was purified by column chromatography (MeOH / DCM) to yield 80 mg (73%) of (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 166.The LCMS-ESI (m / z) calculated for C22H22N4O3S2: 454.1; obtained 455.4 [M+H]+, tr = 3.46 min,1H NMR (400 MHz, DMSO) δ 8.29 (d, J = 2.3 Hz, 1H), 8.23 ​​(dd, J = 8.9, 2.4 Hz, H5 (H7), 8.5 7.6 Hz, 1H), 7.47 (dd, J = 18.4, 8.3 Hz, 2H), 7.36 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 9.0 Hz, 1H), 6.73 (s, 2H - 4), ( 4,98 3.05 (m, 1H), 3.00 (dd, J = 16.3, 8.0 Hz, 1H), 2.61 - 2.54 (m, 1H), 2.04 - 1.89 (m, 1H), 1.38 (t, J Γ = 5.5 Hz), C-13h, M 6H 165.43, 161.42, 144.43, 141.31, 140.70, 138.02, 132.43, 132.20, 128.52, 128.18, 128.08, 130.126.65. 114.25, 103.78, 72.82, 59.25, 34.62, 31.13, 22.14, HPLC Chiral: (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-1-da 5-fodi-yl-indenomium)-3-thiazol-1 eluted in 50% ethanol in hexanes, 99.0% ee, tr = 40.47 min. [000341] (S )-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl) sulfamide 167 was prepared in an analogous manner using (S )-5-(5-(1-amino-2,3-dihydro-1 H-inden-4-yl)thiazol-2-yl)-2isopropoxybenzonitrile 71. HPLC Chiral: 99.1% ee, tr for Senantiomer = 27.67 min. Petition 870210054926, dated 06 / 18 / 2021, pp. 141 / 238 137 / 198 General Procedure 19. Preparation of Indano Ureas [000342] To a stirred solution of CDI (1.7 eq) in DCM (0.16M) was added a stirred suspension of (R)- or (S)-indanoamine (1 eq) and Et3N (3 eq) in DCM (0.16M) and the mixture was stirred for 2 h or until all the indanoamine was consumed. If necessary, additional CDI was added. This solution was added to the appropriate amine and the reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and the pure product isolated after preparative HPLC. [000343] Compounds 50 to 67 and 168 to 205 were prepared using General Procedure 19. (R)-N-((R)-4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2yl)-2,3-dihydro-1H-inden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide (Compound 56) N'N CN .....NH2 CN S' THE .....NH [000344] Prepared using General Procedure 19: A suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride (20.0 mg, 0.04 mmol) and Et3N (14.7 mg, 0.14 mmol) hydrochloride in DCM (0.5 mL) was added to a CDI (13.4 mg, 0.08 mmol) in DCM (0.5 mL) and the mixture was stirred for 2 h at room temperature. The resulting solution was added to the preparative solution of azetidin-3-ol hydrochloride (15.9 mg, 0.14 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The solvent was evaporated and the crude material was purified by preparative HPLC to provide 15 mg (62%) of (R)-N-((R)4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1Hinden-1-yl)-3-(dimethylamino)pyrrolidine-1-carboxamide 56. The calculated LCMS-ESI (m / z) for C28H32N6O2S: 516.2; obtained 517.2 [M+H]+, tr = 2.43 min, 1H NMR (400 MHz, DMSO) δ 8.40 (d, J = 2.4 Hz, 1H), 8.32 (dd, Petição 870210054926, de 18 / 06 / 2021, pág. 142 / 238 138 / 198 J = 9,0, 2,4 Hz, 1H), 7,99 - 7,76 (m, 1H), 7,51 (d, J = 9,2 Hz, 1H), 7,49 - 7,34 (m, 2H), 6,73 (d, J = 8,4 Hz, 1H), 5,32 (d, J = 8,2 Hz, 1H), 5,09 4,80 (m, 1H), 3,86 (dd, J = 14,3, 7,0 Hz, 1H), 3,75 (dd, J = 11,0, 7,5 Hz, 1H), 3,63 - 3,48 (m, 1H), 3,45 - 3,22 (m, 3H), 3,10 (dt, J = 16,5, 8,3 Hz, 1H), 2,82 (t, J = 5,1 Hz, 6H), 2,56 - 2,40 (m, 1H), 2,32 (dd, J = 9,8, 2,5 Hz, 1H), 2,15 - 2,02 (m, 1H), 2,00 - 1,81 (m, 1H), 1,38 (d, J = 6,0 Hz, 6H),13C RMN (101 MHz, CDCI3) δ 167,10, 165,84, 161,80, 145,94, 142,30, 133,54, 133,36, 128,86, 127,82, 126,94, 126,41, 122,72, 115,78, 114,01, 103,72, 72,71,64,71,55,95, 46,76, 44,20, 42,04, 34,06, 31,45, 27,30, 21,90, 21,89. [000345] (S)-N-(( R )-4-(5-(3-cyano-4-isopropoxifenil)-1,3,4-thiadiazol-2-il)2,3-di-hidro-1H-inden-1-il)-3-(dimetilamino)pirrolidina-1-carboxamida 57 foi preparada de maneira análoga utilizando cloridrato de (S )-5-(5-(1-amino2,3-di-hidro-1 H-inden-4-il) -1,3,4-thiadiazol-2-il)-2-isopropoxibenzonitrila. (R)-N-(4-( 5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl) 2,3-di-hydro-1H-inden-1-yl)morpholine-4-carboxamide (compound 58) [000346] Prepared using General Procedure 19. LCMS-ESI (m / z) calculated for C26H27N5O3S: 489.2; obtained 490.2 [M+H]+, tr = 3.54 min, 1H NMR (400 MHz, CDCh) δ 8.20 (dd, J = 8.9, 2.3 Hz, 1H), 8.13 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 7.7 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 7.08 (d, J = 9.0 Hz, 1H), 5.51 (d, J = 7.6 Hz, 1H), 4.83 - 4.56 (m, 2H), 3.71 (dd, J = 10.0, 5.0 Hz, 4H), 3.54 - 3.33 (m, 5H), 3.29 - 3.05 (m, 1H), 2.81 - 2.56 (m, 1H), 1.91 (ddd, J = 16.4, 13.1, 7.9 Hz, 1H), 1.46 (d, J = 6.1 Hz, 6H),13C NMR (101 MHz, CDCh) δ 167.45, 166.17, 162.16, 157.98, 146.58, 142.87, 133.90, 133.77, 129.34, 128.20, 127.29, 126.95, 123.21, 116.06, 114.36, 104.22, 73.03, 66.92, 56.41, 44.54, 34.72, 31.85, 22.25. Petition 870210054926, dated 06 / 18 / 2021, pp. 143 / 238 139 / 198 (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-1-carboxamide (Compound 172) [000347] Prepared using General Procedure 19: CDI (117 mg, 0.72 mmol) in DCM (1 mL) was added to a suspension of (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 72 (150 mg, 0.36 mmol), Et3N (145 mg, 1.44 mmol) and DCM (1 mL) and the mixture was stirred for 2 h at room temperature. The resulting solution was added to the preparative pyrrolidine solution (77 mg, 1.08 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The solvent was evaporated and the crude material was purified by preparative HPLC to provide 110 mg (78%) of (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-1-carboxamide 172.The LCMS-ESI (m / z) calculated for C27H28N4O2S: 472.1; obtained 473.2 [M+H]+, tr = 3.79 min,1H NMR (400 MHz, DMSO) δ 8.28 (d, J = 2.3 Hz, 1H), 8.22 (dd, J = 8.9, 2.4 Hz, H3 (s = 8.5), 8.1 7.3 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.36 - 7.24 (m, 2H), 6.42 (d, J = 8.6 Hz, 1H), 5.29 (q, J = 8.4 Hz, J 1, 1H), H = 4, 3.31 − 3.20 (m, 4H), 3.17 − 2.95 (m, 2H), 2.43 (ddd, J = 10.7, 6.2, 2.8 Hz, 1H), 2.00 − 1.87 (m, J, 1H), 1.47 − = 6.0 Hz, 6H);13C NMR (101 MHz, CDCh) δ 164.79, 160.90, 156.46, 146.16, 141.10, 140.75, 137.75, 171.131.89, 127.71, 127.63,. 126.53, 124.27, 115.92, 113.78, 103.60, 72.34, 55.78, 45.61, 34.87, 30.80, 25.57, 21.81. [000348] (S )-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)pyrrolidine-1-carboxamide 173 was prepared in an analogous manner using hydrochloride of (S )-5-(5-(1-amino-2,3-di-hydro1H-inden-4-yl)thiazol-2-yl)-2-isopropoxybenzonitrile 71 . Petition 870210054926, dated 06 / 18 / 2021, pp. 144 / 238 140 / 198 (R)-N-(4-(2-(3-cyano-4-isopropoxyphenyl)thiazol-5-yl)-2,3-dihydro-1H-inden-1-yl)morpholine-4-carboxamide (Compound 186) [000349] Prepared using General Procedure 19. LCMS-ESI (m / z) calculated for C27H28N4O3S: 488.2; obtained 489.2 [M+H]+, tr = 3.54 min, 1H NMR (400 MHz, DMSO) δ 8.28 (d, J = 2.3 Hz, 1H), 8.22 (dd, J = 8.9, 2.4 Hz, 1H), 8.16 (s, 1H), 7.54 (d, J = 7.5 Hz, 1H), 7.44 (d, J = 9.1 Hz, 1H), 7.36 - 7.24 (m, 2H), 6.89 (d, J = 8.3 Hz, 1H), 5.30 (d, J = 8.2 Hz, 1H), 4.99 - 4.83 (m, 1H), 3.61 - 3.50 (m, 4H), 3.42 - 3.24 (m, 4H) 161.35, 157.93, 146.06, 141.53, 141.16, 138.11, 132.35, 132.20, 128.26, 128.14, 126.90, 124.68, 116.38, 114.20, 103.97, 72.80, 66, 91, 56, 53, 44, 50, 34, 89, 31, 31, 22, 26. General Procedure 20. Preparation of Indanoamines from Indanols [000350] To a flask containing indanol (1 eq) in DCM (0.14M) at 0°C, SOCl2 (2 eq) was added. After stirring for 30 min, the reaction mixture was concentrated in vacuo and placed under high vacuum for 2 h. The resulting crude chloride was dissolved in DMA (0.02M). The amine (3 eq), DIEA (3 eq), and in some cases, NaBr (3 eq) were added, and the resulting reactions were stirred at 55-60°C overnight and purified by preparative HPLC or column chromatography. [000351] Compounds 206 to 219 were prepared using General Procedure 20. 5-(5-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4yl)thiazol-2-yl)-2-isopropoxybenzonitrile (Compound 207) Petition 870210054926, dated 06 / 18 / 2021, pages 145 / 238 141 / 198 [000352] Prepared using General Procedure 20: To a stirred solution of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)2-isopropoxybenzonitrile (20 mg, 0.05 mmol) in DCM (1 mL) thionyl chloride (12.6 mg, 0.106 mmol) was added at 0°C. The reaction was stirred at room temperature for 3 h. The solvent was evaporated and the crude chloride redissolved in dimethyl acetamide (1 mL). Diisopropyl ethylamine (20.5 mg, 0.16 mmol) and ethanolamine (9.7 mg, 0.16 mmol) were added and the reaction mixture was stirred at 70°C overnight. The reaction mixture was rapidly cooled with water (200 µL) and purified by preparative HPLC to provide 11 mg (46%) of 5-(5-(1-(3-hydroxyazetidin-1-yl)-2,3-dihydro-1H-inden-4-yl)thiazol-2-yl)-2isopropoxybenzonitrile 208. The calculated LCMS-ESI (m / z) for C25H25N3O2S: 431.1; obtained 432.1 [M+H]+, tr = 6.48 min (Method 2). 2-fluoro-5-(thiazol-5-yl)benzonitrile (THZ INT-3) [000353] 5-(tributylstanyl)thiazole (1.00 g, 2.7 mmol) in THF (10 mL) was added to 2-fluoro-5-iodobenzonitrile (0.791 g, 3.2 mmol). The solution was degassed with N2 and bis(triphenylphosphine)palladium(II) chloride Pd(Ph)2Cl2 (0.187 g, 0.27 mmol) was added. The solution was further degassed for five minutes before heating at 85°C for 2 h. Upon cooling, the reaction mixture was diluted with saturated NaHCO3 and washed with EA (3 x 50 mL). The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (10% EA / Hexanes) to provide 0.450 g (82%) of 2-fluoro-5-(thiazol-5-yl)benzonitrile THZ INT-3 as a brownish-yellow solid. The LCMS-ESI (m / z) calculated for C10H5FN2S: 204.2; yielded 205.0 [M+H]+, tr = 3.00 min. Petition 870210054926, dated 06 / 18 / 2021, pages 146 / 238 142 / 198 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile (THZ I NT-4) CN CN [000354] To a stirring solution of 2-fluoro-5-(thiazol-5-yl)benzonitrile THZ INT-3 (0.429 g, 2.1 mmol) in acetic acid (10.5 mL) was added potassium acetate (0.412 g, 4.2 mmol). Bromine (0.647 mL, 12.6 mmol) was added dropwise over 10 minutes and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was basified with 1N NaOH and washed with EA and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (20% EA / Hexanes) to yield 0.10 g (30%) of 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4. The LCMS-ESI (m / z) calculated for C-ioH4BrFN2S: 283.1; obtained 284.9 [M+H]+, tR = 3.33 min. 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4yl)thiazol-5-yl)-2-fluorobenzonitrile [000355] Prepared using General Procedure 1. To 5-(2-bromothiazol-5-yl)-2-fluorobenzonitrile THZ INT-4 (0.100 g, 0.35 mmol), tert-butyldimethyl(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1 / - / -inden-1 -yloxy)silane IND INT-8 (0.143 g, 0.38 mmol) and sodium carbonate (0.112 g, 1.1 mmol) in dioxane (1.8 mL) and H2O (0.2 mL) were added tetrakis(triphenylphosphine)palladium (0.041 g, 0.035 mmol). The solution was degassed with N2 and the reaction mixture heated to 85°C for 6 h. Upon cooling, the reaction mixture was diluted with brine and washed with DCM (3 x 100 mL). The layers Petition 870210054926, dated 06 / 18 / 2021, pp. 147 / 238 143 / 198 combined organic compounds were dried over MgSO4, filtered, and concentrated. The crude product was purified by chromatography (30% EA / Hexanes) to yield 0.05 g (32%) of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1 / - / -inden-4-yl)thiazol-5-yl)-2-fluorobenzonitrile as a white solid. The LCMS-ESI (m / z) calculated for C25H27FN2OSSI: 450.6; yielded 451.1 [M+H]+, fa = 4.84 min (Method 3). 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4yl)thiazol-5-yl)-2-isopropoxy-benzonitrile CN CN [000356] Prepared using General Procedure 2. To a solution of 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1 / - / -inden-4yl)thiazol-5-yl)-2-fluorobenzonitrile (0.043 g, 0.095 mmol) in isopropanol (2 mL) was added sodium isopropoxide (0.07 g, 0.090 mmol). The reaction mixture was heated to 60°C for 12 h. Upon cooling, the solvent was removed under a stream of N2 and the crude reaction mixture was carried to the next step without further purification. The LCMS-ESI (m / z) calculated for C28H34N2O2SS1: 490.7, fa = 5.06 min (Method 3). 5-(2-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiazol-5-yl)-2isopropoxy-benzonitrile (Compound 222) CN CN [000357] Prepared using General Procedure 3. Crude 5-(2-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1 / - / -inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile (0.043 g, 0.095 mmol) was added to 4N HCl in dioxane (1.0 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was concentrated under a stream of N2 and the mixture dissolved in MeOH (1.0 mL). The crude product Petition 870210054926, dated 06 / 18 / 2021, pages 148 / 238 144 / 198 was purified by preparative HPLC to yield 0.02 g (43%) of 5-(2(1-hydroxy-2,3-dihydro-1 / - / -inden-4-yl)thiazol-5-yl)-2-isopropoxybenzonitrile 222. LCMS-ESI (m / z): calculated for: C22H20N2O2S: 376.5; obtained 377.1 [M+H]+, fR = 3.31 min. 2-isopropoxy-5-(thiophen-2-yl)benzonitrile (THIO INT-1) ΓΛ [000358] A microwaveable flask was loaded with 5-bromo-2-isopropoxybenzonitrile (200 mg, 0.83 mmol), thiophen-2-ylboronic acid (106.5 mg, 0.83 mmol), potassium carbonate (345.3 mg, 2.49 mmol), and a 3:1 mixture of dimethylethylene glycol / H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirred solution for 10 min. Pd(PPha)4 (20.4 mg, 0.02 mmol) was added and the solution degassed for a further 2 min. The flask was subjected to microwave irradiation at 100°C for 30 min. The solvent was removed and the residue dissolved in EA (10 mL), washed with brine, and dried over MgSO4. The product was purified by chromatography (EA / hexanes) to provide 165 mg (82%) of 2-isopropoxy-5-(thiophen-2-yl)benzonitrile THIO INT-1 as a colorless oil.LCMS-ESI (m / z) calculated for C14H13NOS: 243.1; obtained 266.0 [M+Na]+, fa = 3.90 min, Ή NMR (400 MHz, CDCI3) δ 7.74 (d, J = 2.3 Hz, 1H), 7.69 (dd, J = 8.8, 2.4 Hz, 1H), 7.28-7.23 (m, 1H), 7.19 (dd, J = 3.6, 1.1 Hz, 1H), 7.05 (dd, J = 5.1, 3.6 Hz, 1H), 6.95 (d, J = 8.8 Hz, 1H), 4.65 (dt, J= 12.2, 6.1 Hz, 1H), 1.43-1.37 (m, 6H). 5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile (THIO INT-2) CN CN [000359] To a solution of 2-isopropoxy-5-(thiophen-2-yl)benzonitrile Thioint-1 (160 mg, 0.66 mmol) in anhydrous DMF (5 mL) was added. Petition 870210054926, dated 06 / 18 / 2021, pp. 149 / 238 145 / 198 Freshly crystallized N-bromosuccinimide (118 mg, 0.66 mmol) at 0°C. The reaction mixture was stirred at room temperature for 3 h (longer reaction times and the use of excess NBS caused dibromination). The reaction mixture was diluted with EA (10 mL), washed with water (2 x 10 mL) of brine, and dried over MgSO4. The crude product was purified by silica gel column chromatography (EA / hexanes) to provide 126 mg (60%) of 5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-2 as a white solid. The calculated LCMS-ESI (m / z) for CuHi2BrNOS was 320.9; without M+, tR = 4.26 min. Ή NMR (400 MHz, CDCI3) δ 7.60 (d, J = 2.3 Hz, 1H), 7.53 (dd, J = 8.8, 2.4 Hz, 1H), 6.95 (d, J = 3.9 Hz, 1H), 6.89 (t, J = 6.2 Hz, 2H), 4.60 (dt, J= 12.1.6.1 Hz, 1H), 1.35 (d, J = 6.1 Hz, 6H). 5-(5-(1-(tert-butyldimethylsilyloxy)-2,3-dihydro-1H-inden-4yl)thiophen-2-yl)-2-isopropoxybenzonitrile CN CN [000360] Prepared from 5-(5-bromothiophen-2-yl)-2isopropoxybenzonitrile THIO INT-2 and (±)-((4-bromo-2,3-di-hydro-1H-inden-1yl)oxi)(tert-butyl) dimethylsilane IND INT 8 using General Procedure 1 . LCMS-ESI (m / z) calculated for C29H35NO2SSY: 489.2; does not obtain M+, ír = 8.10 min (Method 1),1H NMR (400 MHz, CDCI3) δ 7.77 (d, J = 2.3 Hz, 1H), 7.71 (dd, J = 8.8, 2.4 Hz, 1H), 7.44 (J, Hz, 1Hz), 7.44 (J, Hz, 1Hz 7.27 (d, J = 4.5 Hz, 2H), 7.17 (dd, J= 12.5, 3.8 Hz, 2H), 6.96 (d, J= 8.9 Hz, 1H), 5.29 (t, J= 7.1 Hz, 1H), = 15.9, 8.8, 2.8 Hz, 1H), 2.95 (dt, J = 16.2, 8.1 Hz, 1H), 2.56-2.36 (m, 1H), 1.94 (dd, J= 12.6, 7.3 Hz, 1H), d 1.01-0.86 (m, 9H), 0.17 (d, J= 9.3 Hz, 6H). 5-(5-(1 -hydroxy-2,3-di-hydro-1 H-inden-4-yl)thiophen-2-yl)-2isopropoxybenzonitrile (Compound 223) CN CN Petition 870210054926, of 18 / 06 / 2021, p. 150 / 238 146 / 198 [000361] To a stirred solution of 5-(5-(1-(tert-butyldimethylsilyloxy)2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile (80 mg, 0.16 mmol) in 1,4-dioxane (1 mL) were added 4N of HCl solution in 1,4-dioxane (1 mL). The reaction mixture was stirred at room temperature for 2 h. The solvent was evaporated and the crude product was purified by chromatography (EA / hexanes) to provide 26 mg (40%) of 5-(5-(1-hydroxy-2,3-dihydro-1 / - / -inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile 223 as a white solid.A LCMS-ESI (m / z) calculada para C23H21NO2S: 375,1; obteve 398,1 [M+Na]+, ír = 3,96 min,1H RMN (400 MHz, CDCI3) δ 7,77 (d, J = 2,3 Hz, 1H), 7,71 (dd, J = 8,8, 2,4 Hz, 1H), 7,53 - 7,45 (m, 1H), 7,38 (d, J = 7,4 Hz, 1H), 7,30 (t, J = 7,5 Hz, 1H), 7,19 (q, J = 3,8 Hz, 2H), 6,97 (d, J = 8,9 Hz, 1H), 5,28 (t, J = 6,1 Hz, 1H), 4,66 (dt, J= 12,2, 6,1 Hz, 1H), 3,28 (ddd, J= 16,2, 8,5, 4,7 Hz, 1H), 3,11-2,91 (m, 1H), 2,53 (dddd, J= 13,1,8,2, 6,9, 4,7 Hz, 1H), 2,08-1,92 (m, 1H), 1,57 (s, 1H), 1,41 (d, J=6,1 Hz, 6H),13C RMN (101 MHz, CDCI3) δ 159,37, 146,65, 142,74, 141,52, 140,36, 131,55, 131,08, 130,96, 130,79, 127,79, 127,54, 126,67, 123,82, 116,57, 114,40, 103,82, 76,59, 72,43, 36,07, 30,88, 22,08. 5-(5-( 1 -(2-hidroxiethylamino)-2,3-di-hidro-1 H-inden-4il)tiofen-2-il)-2-isopropoxibenzonitrila (Composto 224) [000362] Prepared using General Procedure 20 from 5-(5-(1-hydroxy-2,3-dihydro-1 / - / -inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile and ethanolamine. LCMS-ESI (m / z) calculated for C25H26N2O2S: 418.2; obtained 419.1 [M+H]+, fR = 2.73 min. (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3dihydro-1H-inden-1-ylcarbamate CN CN Petition 870210054926, dated 06 / 18 / 2021, pp. 151 / 238 147 / 198 [000363] A 20 mL microwaveable flask was loaded with (R)tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-hinden-1-ylcarbamate IND INT-18 (44 mg, 0.12 mmol), 5-(5-bromothiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-2 (40 mg, 0.12 mmol), potassium carbonate (51 mg, 0.37 mmol), and a 3:1 mixture of dimethylethylene glycol / H2O (2 mL). The reaction mixture was degassed by bubbling N2 gas through the stirred solution for 10 min. Pd(PPh3)4 (10.1 mg, 0.008 mmol) was added and the solution degassed for a further 2 min. The flask was subjected to microwave irradiation at 100°C for 30 min. The solvent was removed and the residue dissolved in EA (10 mL), washed with brine, and dried over MgSO4. The product was purified by chromatography (EA / hexanes) to provide 15 mg (51%) of (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate as a whitish solid.LCMS-ESI (m / z) calculated for C28H30N2O3S: 474.2; did not obtain M+, ír = 4.43 min,1H NMR (400 MHz, CDCI3) δ 7.76 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.45 (dd, J= 6.3, 2.2 Hz, 1H), 7.27 (d, J= 6.6 Hz, 2H), 7.17 (dd, J = 11.9, 3.8 Hz, 2H), 6.97 (d, J = 8.9 Hz, 1H), 5.30 - 5.11 (m, 1H), 4.78 (d, J= 8.6 Hz, 1H), 4.66 (dt, J = 12.2, 6.1Hz, 1H), 3.18 (ddd, J = 16.1, 8.7, 3.4 Hz, 1H), 3.02 (dt, J= 16.1,8.1 Hz, 1H), 2.68 - 2.51 (m, 1H), 1.90 - 1.73 (m, 1H), 1.47 (d, J = 8.2 Hz, 9H), 1.41 (d, J = 6.1 Hz, 6H). (R)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2isopropoxybenzonitrile (Compound 225) CN CN [000364] Prepared using General Procedure 5. To a stirred solution of (R)-tert-butyl 4-(5-(3-cyano-4-isopropoxyphenyl)thiophen-2-yl)-2,3-dihydro-1H-inden-1-ylcarbamate (15 mg, 0.03 mmol) in 1,4-dioxane (1 mL) were added 4N of HCl solution in 1,4-dioxane (0.5 mL). A Petition 870210054926, dated 06 / 18 / 2021, pages 152 / 238 The reaction mixture 148 / 198 was stirred at room temperature for 16 h. The solvent was evaporated and the resulting solid was dissolved 1:1 in DMSO:MeOH (1 mL) and purified by preparative HPLC to provide 10 mg (90%) of (R)-5-(5-(1-amino-2,3-dihydro-1 / - / -inden4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile 225 as a white solid. The calculated LCMS-ESI (m / z) for C23H22N2OS was 374.2; it was obtained as 358.1. [MNH2]+, ír = 2.69 min. 5-(4-bromothiophen-2-yl)-2-isopropoxybenzonitrile (THIO INT-3) Br CN [000365] A 2 mL microwave flask was loaded with 2,4-dibromothiophene (20 mg, 0.08 mmol), (3-cyano-4-isopropoxyphenyl)boronic acid (17 mg, 0.08 mmol), potassium carbonate (35 mg, 0.25 mmol), and a 3:1 mixture of DME / H2O (4 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPhs)4 (7 mg, 0.006 mmol) was added and the solution degassed for a further 2 min. The flask was subjected to microwave irradiation at 70°C for 30 min or until the starting material was consumed. 5-(4-bromothiophenyl-2-yl)-2-isopropoxybenzonitrile THIO INT-3 was used in the next experiment without purification. LCMS-ESI (m / z) calculated for CuHi2BrNOS: 320.9; M+ not observed, ír = 4.15 min. 5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4yl)thiophen-2-yl)-2-isopropoxybenzonitrile Petition 870210054926, dated 06 / 18 / 2021, pp. 153 / 238 149 / 198 [000366] Prepared from 5-(4-bromothiophene-2-yl)-2isopropoxybenzonitrile THIO INT-3 (0.08 mmol) and tert-butyldimethyl((4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-di-hydro-1H-inden-1yl)oxy)silane IND INT-8 (31 mg, 0.08 mmol) using General Procedure 1, to provide (102 mg, 302 mg) during two steps 5-(4(1-(( tert -butyldimethylsilyl)oxy)-2,3-di-hydro-1H-inden-4-yl)thiophen-2-yl)-2isopropoxybenzonitrile. A LCMS-ESI (m / z) calculated for C29H35NO2SSi: 489.2; does not obtain M+, tr = 6.66 min (Method 1),1H NMR (400 MHz, CDCl3) δ 7.76 (d, J = 2.3 Hz, 1H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.36 - H 7.25 (m, 2H), 7.25 to 7.19 (m, 1H), 6.96 (d, J = 8.9 Hz, 1H), 5.28 (t, J = 6.9 Hz, 1H), 4.73 to 4.50 (m, 1H), 3.09 (dd, J = 8.8, 8.8 Hz, 1H), 2.88 (dt, J = 16.0, 8.1 Hz, 1H), 2.47 2.30 (m, 1H), 1.96 - 1.81 (m, 1H), 1.40 (d, J = 6.1 Hz, 6H), Hz, 6H). 5-(4-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2isopropoxybenzonitrile (Compound 226) [000367] Prepared using General Procedure 3. To a solution of 5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile (17 mg, 0.03 mmol) in THF (1 mL) was added 1M TBAF solution in tetrahydrofuran (0.3 mL, 0.3 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by preparative HPLC to yield 8 mg (46%) of 5-(4-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile 226 as a white solid. LCMS-ESI (m / z) calculated for C23H21NO2S: 375.1; obtained 398.1 [M+Na]+, tr = 3.84 min;1H NMR Petition 870210054926, dated 06 / 18 / 2021, pages 154 / 238 150 / 198 (400 MHz, CDCI3) δ 7,78 (d, J = 2,3 Hz, 1H), 7,72 (dd, J= 8,8, 2,4 Hz, 1H), 7,43 - 7,36 (m, 2H), 7,35-7,28(m, 1H),7,26 (d, J= 1,4 Hz, 1H), 7,24 (s, 1H), 7,06-6,89 (m, 1H), 5,29 (t, J= 6,1 Hz, 1H), 4,77-4,49 (m, 1H), 3,20 (ddd, J = 16,0, 8,4, 4,7 Hz, 1H), 3,01 - 2,86 (m, 1H), 2,50 (dddd, J = 13,0, 8,1, 6,8, 4,7 Hz, 1H), 2,11 - 1,88 (m, 1H), 1,58 (s, 1H), 1,41 (d, J= 6,1 Hz, 6H);13C RMN (101 MHz, CDCI3) δ 159,51, 146,35, 142,55, 142,00, 140,88, 133,16, 131,79, 131,24, 128,14, 127,69, 127,56, 124,16, 123,54, 122,06, 116,54, 114,39, 103,84, 76,68, 72,45, 36,28, 30,50, 22,08. ((4-(4-bromotiofen-2-il)-2,3-di-hidro-1 H-inden-1-il)oxi)(tercbutii) dimetilsilano (THIO INT-4) [000368] Prepared using General Procedure 1. A 2 mL microwave flask was loaded with 2,4-dibromothiophene (15 mg, 0.06 mmol), tert-butyldimethyl((4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)oxy)silane IND INT-8 (23 mg, 0.06 mmol), potassium carbonate (26 mg, 0.18 mmol) and a 3:1 mixture of DME / H2O (2 mL). The reaction mixture was degassed by bubbling N2 through the stirred solution for 10 min. Pd(PPh3)4 (5 mg, 0.004 mmol) was added and the solution degassed for a further 2 min. The flask was subjected to microwave irradiation at 70°C for 30 min or until the starting material was consumed. The resulting ((4-(4-bromothiophen-2-yl)-2,3-dihydro-1-Hinden-1-yl)oxy)(tert-butyl)dimethylsilane THIO INT-4 was carried over to the next experiment without further testing and purification. The calculated LCMS-ESI (m / z) for CigH25BrOSSi: 408.1; no M+ obtained, Ir = 6.50 min (Method 1). 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2Petition 870210054926, of 18 / 06 / 2021, p. 155 / 238 151 / 198 yl)benzonitrile CN [000369] A suspension of 5-bromo-2-isopropoxybenzonitrile (200 mg, 0.83 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (233.7 mg, 920 mmol), and potassium acetate (246 mg, 2.5 mmol) in anhydrous 1,4-dioxane (100 mL) was degassed by passing N2 through the solution for 30 min. PdCl2(dppf).CH2Cl2 (136 mg, 0.16 mmol) was added and the reaction mixture was heated to 85°C for 6 h. The solvent was removed under vacuum and the residue was dissolved in EA (100 mL) and filtered through celite. The filtrate was washed with water and brine, dried over MgSO4, and purified by chromatography (EA / hexanes) to provide 40 mg (13%) of 2-isopropoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile as a white solid.LCMSESI (m / z) calculated for C16H22BNO3: 287.2; obtained 288.2 [M+H]+, tR= 4.07 min,1H NMR (400 MHz, CDCI3) δ 7.97 (d, J = 1.5 Hz, 1H), 7.88 (dd, J= 8.5, 1.7 Hz, 1H), 6.91 (d, J= 8.5 Hz, 1H), 4.67 (dt, J = 12.2, 6.1 Hz, 1H), 1.38 (d, J= 6.1 Hz, 6H), 1.30 (s, 12H). 5-(5-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4yl)thiophen-3-yl)-2-isopropoxybenzonitrile (THIO I NT-5) [000370] To the crude reaction mixture containing ((4-(4-bromothiophen-2-yl)2,3-dihydro-1H-inden-1-yl)oxy)(tert-butyl)dimethylsilane THIO INT-4 (0.12 mmol) in a 3:1 DME / H2O mixture (4 mL) was added 2-isopropoxy-5(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (17.9 mg, 0.06 mmol) and the solution was degassed for 2 min. Pd(PPhs)4 (7 mg, Petition 870210054926, dated 06 / 18 / 2021, pp. 156 / 238 152 / 198 A 0.006 mmol solution was added and the reaction mixture degassed for a further 2 min. The reaction mixture was heated under microwave conditions at 100°C for 30 min. The reaction mixture was diluted with EA (10 mL), washed with water and brine, and dried over MgSO4. The crude product was purified by silica gel column chromatography (EA / Hexanes) to provide 12 mg (40%, in two steps) of 5-(4-(1-((ferc-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-5. The calculated LCMS-ESI (m / z) for C29H35NO2SS1 was 489.2; no M+ obtained, λr = 6.66 min (Method 1). 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-3-yl)-2isopropoxybenzonitrile (Compound 227) [000371] Prepared using General Procedure 3. To a solution of 5-(4-(1-((tert-butyldimethylsilyl)oxy)-2,3-dihydro-1H-inden-4-yl)thiophen-2-yl)-2-isopropoxybenzonitrile THIO INT-5 (12 mg, 0.02 mmol) in THF (1 mL) was added 1M TBAF solution in tetrahydrofuran (0.2 mL, 0.2 mmol) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and purified by preparative HPLC to yield 3 mg (22%) of 5-(5-(1-hydroxy-2,3-dihydro-1H-inden-4-yl)thiophen-3-yl)-2-isopropoxybenzonitrile 227 as a white solid. LCMS-ESI (m / z) calculated for C23H21NO2S: 375.1; obtained 398.1 [M+Na]+, fR= 3.85 min;1H NMR (400 MHz, CDCI3) δ 7.77 (dd, J = 6.9, 2.2 Hz, 1H), 7.74 - 7.68 (m, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.45 - 7.36 (m, 1H), 7.36 - 7.28 (m, 1H), 7.27 - 7.22 (m, 2H), 7.10 6.74 (m, 1H), 5.37 - 5.15 (m, 1H), 4.67 (dt, J = 12.2, 6.1 Hz, 1H), 3.90 (ddd, J= 16.2, 8.5, 4.7 Hz, 1H), 3.14-2.98 (m, 1H), 2.66-2.40 (m, 1H), 2.09 - 1.87 (m, 1H), 1.57 (s, 1H), 1.41 (d, J = 6.1 Hz, 6H). Petition 870210054926, dated 06 / 18 / 2021, pages 157 / 238 153 / 198 [000372] The selected compounds and their corresponding analytical data are shown in Table 1, where LCMS data were collected using Method 2 (see General Methods). Enantiomeric purity was determined for important intermediates and selected final compounds and was estimated from the synthesis of the remaining compounds. Table 1 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) nn dl Λ III 0H N 1 8.53 nn III 0H N 2 8.54 oo I 3 8.52 1 í 1 r n'N / ==> 1 n'1 6, / =^ \^'NH2 1 1 5 6.08 Petition 870210054926, dated 06 / 18 / 2021, p. 158 / 238 154 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) o __ / O— z I hJ 6 5.98 1 f YqY Γ n'N / =^ o J / Λ \1 °h \ \Y*N 1 H >1 7 µθ A 7.82 \__ / OH v-OH 8 7.78 CM I zz A / \ W ÇX T ^z Y 9 6.18 1 f Υ'Ο'^ Γ NN / =^ Y^S^O 0 J / Λ A / nh2 1 H 10 6.18 / γY_N T <0 / A ^ΝΆ_η H VOx 11 8.68 Petition 870210054926, dated 06 / 18 / 2021, p. 159 / 238 155 / 198 STRUCTURE COMPOUND NUMBER LCMS RETAIN TIME (min) NZ ° 12 8.70 NN / =xi ? 1 Λ J / \ ü n. II HN 13 6.43 -7 / yUI ° A / i Njy NZ ° H x 14 8.26 ,γγΥΝ S^Y-^% / / jQ N \__1 o * nA H x 15 8.26 / N^n NZ ° Η O / 16 9.26 <f~VY^T z A / \ z^ / w Ol T ^T° 17 6,19 Petition 870210054926, dated 06 / 18 / 2021, p. 160 / 238 156 / 198 ESTRUTURA NÚMERO DO COMPOSTO TEMPO DE RETENÇÃO LCMS (min) i £ n'N J / \ OH T A^·ν 1 HN 18 6,09 “£ O / ^'N °a yy li jO n \ 1 H 19 6,42 1 £ 1 r NL / =\ v^yi) J ( \ ,o^ i H 20 6,48 1 f 1 N'N Ai tf 1 H ° J 21 6,34 “£ _ / Γ1ΛΝ °a yy ii / / fO N ( γ I H P O 22 6,30 i £ N n'N r=. A-AO fA J / \ / NA V^N tf H ° 23 6,50 Petition 870210054926, de 18 / 06 / 2021, pág. 161 / 238 157 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) N'N. / => Á AJ / \ ο γ ΝΆΑ II H ° N 24 6.35 - / A.ZT z Y / \ zx ω Ol T Ύ° 25 6.31 τ ο Γ ΖΙ Ζ=ζ \ / —=ζ ο 26 6.44 ΛΑ / / Ν yx ιι Jxj Ν \ / \^γ / ΟΗ Η Π Ο 27 6.41 ν-ν Λ / Ί η ιι Ν \ W Η k # Ν Ν^7 28 6.21 1 ^0 ω^ζ \ / ^\ / ζ ΙΖ^ γ # L ζι 29 6.10 Petition 870210054926, de 18 / 06 / 2021, pág. 162 / 238 158 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) / o / / ,__, \ —o (Λ Al I ~'T° 30 6.81 z—— Yz <\Y Ώζ) ω ri 1 ^YY 32 6.32 nn AA / A oo ii / 1 / HN 33 8.84 A #γ. γΝ o-Ç νγ Η / 0 N ( 1 \___1 O % II HN-S— II O 34 8.80 A / ^ύΥ'ν / / When n < / \__1 o \ II HN-S^, °Y 35 9.10 Petition 870210054926, dated 06 / 18 / 2021, p. 163 / 238 159 / 198 STRUCTURE COMPOUND NUMBER LCMS RETAIN TIME (min) NN J! 1 Pp V ° r ÍA V5 ili h SN o— 36 9.13 / OH N \ / O / \ H ° 37 6.52 TQ oz Ο=ω=ο z={ / \ zx ω T ^z 38 6.54 “ / ρ—\ / li / ΓN oy / 39 6.46 nn JI A / j III Η θ o N 40 8.37 oy^A / / N'N \= / \ II n / / \ ° '—( O VoH II / HN-S—' II O 41 8.33 Petition 870210054926, dated 06 / 18 / 2021, p. 164 / 238 160 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) nn aAjs । \\ H^OJN 42 8.58 “X ZA M ° \ / —\ 11 / { jO n < r P / M ? M HN-S—' 45 8.21 <Y z^ 1 *0 ω^ζ \ / $Ύ) Ο=ω=ο Ο τ 46 8,18 n'N / =. 1 MZ^s^CZ^ 0 JL Ji À / \ s \Y^i<Ynh2 II H° N 47 829 Petition 870210054926, dated 06 / 18 / 2021, pp. 165 / 238 161 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) η )= / / / 70 N Cj O 48 8.26 Z^ 1 10 ω^ζ \ / .. / z IZ z^ 49 6.23 00 u / Ώ N ( f \J o Η N—। ü,-« o 50 7.75 NN / =ç i J^0S0^? Petition 870210054926, dated 06 / 18 / 2021, pp. 166 / 238 162 / 198 STRUCTURE COMPOUND NUMBER LCMS RETAIN TIME (min) 1 [AH? ° AA As / Ν ' , ii H a / N 53 8,92 / / jO N f T \__1 o ^nA HN~ak / ^OH 54 7,61 AX 1 h n'N / =_ A^s^Ç) o A ΑΑνΧ^νΑ / H,6^ο5 i > aJ n < A \__1 o ^nA Η N—, A / 'A \ 56 6,26 aX 1 h nA / =ao J (VA / x / A a^n? n A“n ! HA / xd 57 6,30 ΑαΑ'ϊ A / sA^58A H aa8 N f. Petition 870210054926, dated 06 / 18 / 2021, p. 167 / 238 163 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) AUD 59 8.43 kJ N 7 1 HVN 1 P Where N n'N J anwhH 60 8.02 A γο-ν}O_ / N oY / \ 61 7.98 a <i ω^ζ z ιζ'α az^0 o t 62 7,75 al na =x a^s^o can^na i h aaah 63 7,79 1 =\ aa^s^c ^ a v>n^nA ! H OH N 64 7,60 Petition 870210054926, dated 06 / 18 / 2021, pp. 168 / 238 164 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) / / N'n ° \ / —\ 11 / IJ N f T \__ / OH lZ OH 65 7.55 ° \ / —\ d >= / ZO N < T \__ / O n^ Η N / 66 8.55 1 Γ 1 nn / ==, 0>n^nx H ' 67 8.58 ΛΑ / N oA 1L jO N <T^ \ / O Tj-A H O 68 9,25 í Αχ 1 N^\ / =Λ y-sHZ 1 69 9,11 \γ··^0Η N 70 9,12 Petition 870210054926, dated 06 / 18 / 2021, pp. 169 / 238 165 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) CN I zz^ / \= / —=z __o 71 6.20 £ AAn A^s AA / OH H 74 8.22 rm 1 AA^S ? T V-NA-NH^ / / / HN 77 6.47 Petition 870210054926, dated 06 / 18 / 2021, pp. 170 / 238 166 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) ...... N 78 6.45 79 6.42 °xOHNz N—' NH2 80 6.44 II HN 81 6.62 • . II HN 82 6.63 N 83 9.99 N 84 9.98 NH 85 6.93 Petition 870210054926, dated 06 / 18 / 2021, p. 171 / 238 167 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) Χ,ΑΟ \ III h N 86 6.92 aA JAAA 1 H II N JH) 'z_X ° \ÀNXo / H 90 9,76 Âv VV / x.OH 'll η 91 6,39 , TKaa Λ Lj s χτ o A / 1 1 vAm / -x^oh III h N 92 6,34 CT ω ω Petition 870210054926, dated 06 / 18 / 2021, p. 172 / 238 168 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) / JAn A jTjs A / T / / / HN 94 6.62 A XJ 71 A« H ill N 95 6.47 A Ajls)A oy' / A 5 / χlí6 Q ^AO AO(A o A \Α>ιΑΎ II H 0 N 97 6.63 a α II H 0 N 98 6.54 ^AAa\ A. fAsAr cA\A / Ί T Α-'^'Κ Hl H 5 99 6'TAHH ' / -) 100 6.83 A υ α ο '-A^n A II H ° N 101 6.66 Petition 870210054926, dated 06 / 18 / 2021, pp. 173 / 238 169 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) o7* ω \ Cij A z—, -AI 102 6.34 Νγ / AAAA °H ΑΆ / AA\ Αχ / ΑΥ ili YNH o 103 6.36 NA OH t ΑΎ.....ú 0 \ / >nA II H 0 N 104 6.28 A0X 1 h ΉΛαα °h AsAA ó A ( \ x^ / NA \x^NA 1 H 0 105 6.31 A0X 1 NA / =\ H(? AAA 1 H 0 4 106 6.43 Νγ , ^A AAA AA Ί / s aJ Ο'Ά Xl [ NH / Vx,^\xN. j li «A 107 6.78 λΆ 1 AA^YWX^ A AA Petition 870210054926, dated 06 / 18 / 2021, pp. 174 / 238 170 / 198 STRUCTURE COMPOUND NUMBER RETENTION TIME LCMS (min) 110 6.51 N 111 9.24 N 112 9.25 N 113 9.54 N 114 9.56 115 9.44 N 116 9.55 N 117 9.72 Petition 870210054926, dated 06 / 18 / 2021, pp. 175 / 238 171 / 198 STRUCTURE NUMBER OF COMPOUND RETENTION TIME LCMS (min) C* XX % AA ih A 'ò N 118 9,70 1 fX z °V <1 Va N 119 10,32 Λ jCis>CI wO 120 10,33 XXj s >x III N 121 7,15 ^ΧΧαλ jjy^sy# li Al '8 N 122 6.99 NX X„X jw °^r / | °x / ° / WxJSÇ / ÍÍ Η Γν^θ' / Χ XV (I 9. ^NH lí H' '0 N 125 6,72 Petition 870210054926, 18 / 06 / 2021, pág. 176 / 238 172 / 198 STRUCTURE NUMBER OF COMPOUND RETENTION TIME LCMS (min) , Kza AAj χ / C \ '9 III ''YSx^NH NH | 126 6.89 ΛΛ Λ xz (| A 'P III NH \A 127 7.04 ^xJTWa A fisCC III h' '6 N 128 6.90 ^xTIya / Pi SW ΓΛ cá ° it rr 6 N 129 6.95 AA rxJ OAX (J / / ° ill NH Ly 130 715 Λ jTi5)^ r\ °^r < i ill h' '6 N 131 6,73 NX A kvk OH AXk ζχ ν- Ν / 'ΝΑ Ν Η .....ΟΗ 133 6.90 Petition 870210054926, 18 / 06 / 2021, pág. 177 / 238 173 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) Aaj s / r Ο V II ^VYnA n HX / OH 134 6.88 cC^ Az ω j Co ω' xo oz T ro 135 6.27 CN IZ ò T o z, Γ z z ω < / Y^^^z 136 6,24 i OIy X X í s \ 1 oAA Az 1 \ J °'° * 'Β'^ϊΛ-ν' Y \ 137 6,78 A-vYt / ( I °\ / O « .....N / 138 6,78 Y^A XX ° '•yX y li rr 'b N 139 7,09 i AaA Xk 1 » s kfe- / °γχ Xi °''? ih N H XX 140 7,25 Petition 870210054926, of 18 / 06 / 2021, p. 178 / 238 174 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) δ.....QL° ° ZI Orí V ω z^ / _ 141 6.81 OH III A 'o N ϋθ Az° ω( $X° AOI 144 6.95 Λ ArOH Λ / Α <1 °v^AA ill B' '8 N 145 6.72 z=;—Λ} Az ω J Co wí $x° / > o I 146 6.84 A. XPs^ / l / o x N 17 ° s' ox )ω A'zi w Γ ω X«z 148 7.02 Petition 870210054926, of 18 / 06 / 2021, p. 179 / 238 175 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) y AXry / Ύ c> p / AA 's' ill n -y. NM 149 6.90 Az ω j Qo Σ<Ο ω( xo X o I 150 6.88 z-.. , yA yA A„X fi O °v° ill YN Anh 151 6.83 ^Vy ozIZ,o Ο OT ^73 Í^0 6. ω( O —-z \ 153 6.52 Na z , y^A AO A Xjj sa?0 r ON Ύ oi 154 9.50 / P] s λΑ AAa Af %y / A lí H '° 0 N 155 9.48 O^ 5 o Z^45 yz Petition 870210054926, dated 06 / 18 / 2021, p. 180 / 238 176 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) / F ° / 1 0 U LI H 1 N 157 9.50 TOF ,<O ° > T CjQ 1 ω zx __o 158 8.73 o χχ I2^O 'W o T 159 8.69 o Xz ω 1 ¥ o I 160 8.71 / Jln 1 Fi^8 FF ° / 1 0 U lí} H X '0 j X^ 461 ^o οχχ / η o I. I Γ X, II N xn Π N Η Ο o 162 8.89 1 F / / ^s 'Lz ____-°h oA / Λγ o / / II % ¥ n' H 0 0 NHX Xx %^S 8.39 164 8.66 Petition 870210054926, dated 06 / 18 / 2021, p. 181 / 238 177 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) , III h IN 1 168 9.05 nA y 8 λ .. ü H 1 169 9.06 AXXs Λ? ° Ύ Ui h \1 N u OH 170 7.95 axaA^\ 1 Ai s / la A°VOA III η \Λ Ν ΊΟΗ 171 7.93 Petition 870210054926, dated 06 / 18 / 2021, pp. 182 / 238 178 / 198 STRUCTURE COMPOUND NUMBER RETENTION TIME LCMS (min) / X a Aza A AA? ° Ύ (JA / / / Η \ / NA / 172 9,40 / X λΎυ\ j írs, / Λ V a I 1 / aAA / / / H \ / N '— / 173 9,41 / Pt s \La Λν AA ill H 0.....0H NA 174 8,01 - TAza / / Y[ S^AA Λ Y ai Λ ιίι H nA°h NA 175 7.99 AAa i / / -1 / AAAA ill H O-0H NA 176 8.02 xxaAa i (Pt'sAV A°VAA ιίι Ή lA0H NA 177 8.02 / xÃAza 1 ipvs 7 Y Ya III H NP.....NH2 n A / 178 6.53 Petition 870210054926, dated 06 / 18 / 2021, pp. 183 / 238 179 / 198 STRUCTURE COMPOUND NUMBER RETENTION TIME LCMS (min) III H \ yNH2 179 6.54 ill H >NH2 N 180 6.42 , 181 6.45 III H NL 182 6.51 .....,. 183 6.62 N λ 184 6.55 ill N Nv >.....\ N x 185 6.57 ..... 186 8.87 Petition 870210054926, dated 06 / 18 / 2021, pp. 184 / 238 180 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) Λ° VQL· ih η ON % / O 187 8.87 xJln Oa xx AHI । N \ / NH 188 6.42 / x α3~ζ=λ A°V Ü 1« h OH N %zNH 189 6.39 ω \ pO IZ >° 0 / 190 6.60 / o M ZI z=^ \= / _ 191 6.57 x-xa3-ar Λ V Cl  XX 'll HI N 1 192 6.65 / xÃlVR í (T^ls ΛοΛτ <Λ a 1 193 6.66 Petition 870210054926, dated 06 / 18 / 2021, pp. 185 / 238 181 / 198 STRUCTURE COMPOUND NUMBER RETENTION TIME LCMS (min) ZgY\ a? A'z IZ >° P o I 194 8.41 >° P o I 195 8.41 ^J / AaA i fv saJ I Av / / / HI N PA 196 8.39 rv / A H u T ^A^oh n PA 197 8.42 Λ AA ° Ύ Ο'Λ-γOH NA 198 8.45 IO b °A ZI z^ / V— / __^o 199 8.43 ó^ zs— ^~c / ^z IZ >° o T 200 8.59 Petition 870210054926, of 18 / 06 / 2021, p. 186 / 238 182 / 198 STRUCTURE NUMBER OF COMPOUNDS LCMS RETENTION TIME (min) 1 f ís0 / Y α YJ, nY 0 / / / HI II n 201 8.61 í í / si / Y oy .. ΥΑγ N AYqh 202 8.17 IO 0 0 0 _ _ _ 20 - ZI-2 8.15 YU00 Α°ν u A ii η ns 204 9.61 1) / --Ç O z—í °Y ZI z Y \=- / — _ 205 9.62 Υγ^Υ^ vYnY II N 206 6.80 / Αθγ II Λ Η N 27 ^U 6.47 Petition 870210054926, of 18 / 06 / 2021, p. 187 / 238 183 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) Λί MM Ay Mn^ 1 \l 208 6.93 1 f 1 Mn Ay M-nA^oh 1 209 6.53 1 f Γ N^\ / =\ MΜ Μ Μ Μ 2016 AÍ 1 JW 'Ύ'Ν^^ΝΗ, 1 ° 211 5,76 .A 1 r JK) NN H2 1 212 5,82 1 í r N^\ / =\ Ύί-? ' °Ό 213 6.96 1 r JW Moon 1 214 6.62 Petition 870210054926, of 18 / 06 / 2021, p. 188 / 238 184 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) 6.65 1 f aa r NA / =\ A xp XAnAA 1 HJ 218 7.45 1 Ar2 A~? AA A °v,° III H nh N / 219 6.67 zdA Zaa? oAA < \ —li ^'A qx W h AA N 220 6.65 XA\ 1 Pr5 i / r AA III HN 221 6.58 Petition 870210054926, dated 06 / 18 / 2021, pp. 189 / 238 185 / 198 STRUCTURE COMPOUND NUMBER LCMS RETENTION TIME (min) 222 8.16 .s. / «AA Z VN ζγΟΗ 1 f A^q-^A r vAAQ \ / AqH J 223 9.88 1 jO AqAg II N / \ OH A^n H 224 6.88 1 Γ 1 N yQ~O \ANH2 225 6.83 Tj hA rVO sa AA Y^-QH 226 9.68 1 / A^q^ ΎΑΑ / δ II N 227 9.68 Biological Assays Test Procedures Petition 870210054926, dated 06 / 18 / 2021, pp. 190 / 238 186 / 198 Generation of S1Pi-mediated inhibition of cAMP reporter assay [000373] A mammalian expression plasmid containing S1Pi / EDG1 cloned into pcDNA3.1 was acquired from the Missouri S&T cDNA Resource Center. The nucleotide and amino acid sequence of human S1Pi / EDG1 are published in Hla and Maciag (J Biol Chem, 265(1990), 9308-9313). S1Pi / pcDNA3.1 was transfected into the CRE-bla CHO K1 cell line (Invitrogen), and stable single-cell clones were selected using standard techniques. Functional S1Pi / EDG1 receptor expression was confirmed by cell surface FACS with an S1Pi antibody (R&D Systems, clone 218713) and S1Pi-mediated inhibition of Forskolin-induced cAMP. Essay by reporter S1P1 CRE-bla CHOK1 - characterization of S1P1 agonists [000374] Cells were seeded in 384-well black-walled / transparent-bottomed plates at 104 cells / well / 19.5 μl of assay medium (DMEM-phenol-free, 0.5% charcoal-extracted serum / dextran, 2 mM glutamine, 0.1 mM NEAA, 1 mM NaPyruvate, 25 mM Hepes) and incubated for 18 ha at 37°C in 5% CO2. Dose-response curves (10 points) were generated at 10 mM Hepes, 0.1% Pluronic F127, in the presence of Forskolin. Cells were treated with 0.5 μl of compound in the presence of 2 μM Forskolin for 4 ha at 37°C. The FRET-based fluorescent β-lactamase substrate (LiveBLAzer®-FRET B / G Loading Kit CC4-AM; Invitrogen) was prepared according to the manufacturer's instructions and incubated with cells for 2 h at room temperature. Plates were read at Ex:410 / Em:458 and Ex:410 / Em:522, and the response ratio was determined. Data were analyzed by non-linear regression to determine the EC50 for forskolin-induced cAMP inhibition. Specificity over other S1P receptors [000375] To evaluate the specificity of the compound in other Petition 870210054926, dated 06 / 18 / 2021, pp. 191 / 238 187 / 198 S1P receptors, the following cell lines were used: SIP2 CRE-bla CHOK1, S1P3-Gα15 NFAT-bla HEK293T (Invitrogen), S1P4bla TANGO U2OS (Invitrogen), S1P5-bla TANGO U2OS (Invitrogen). The same assay performed for S1Pi was used, but without Forskolin. The S1P4 and S1P5 assays were performed in FreeStyle Expression medium (Invitrogen). S1P5 cells were incubated for 48 h before treatment with the compound. S1Pi Activity Reported [000376] The activity data for selected S1Pi agonists are shown in Table 2. The activity range is indicated as follows: ++++ denotes agonist activity <0.05 nM. +++ denotes agonist activity between 0.05 and 0.50 nM, and ++ denotes agonist activity between 0.50 and 5.00 nM, and + denotes agonist activity > 5.00 nM. N / A denotes not available. Table 2 COMPOUND NUMBER ACTIVITY S1Pi 1 +++ 2 +++ 3 ++ 4 ++ 5 ++ 6 ++ 7 ++++ 8 +++ 9 +++ 10 +++ 11 +++ 12 ++ 13 ++ 14 +++ NUMBER OF THE COMPOUND ACTIVITY S1Pi 115 +++ 116 ++ 117 +++ 118 +++ 119 +++ 120 ++ 121 ++ 122 ++ 123 ++ 124 ++ 125 ++ 126 ++ 127 ++ 128 + Petition 870210054926, dated 06 / 18 / 2021, pp. 192 / 238 188 / 198 COMPOUND NUMBER ACTIVITY S1Pi 15 +++ 16 ++ 17 +++ 18 ++ 19 ++ 20 ++ 21 ++ 22 +++ 23 ++ 24 ++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 ++ 31 +++ 32 ++++ 33 +++ 34 +++ 35 +++ 36 +++ 37 ++ 38 ++ 39 +++ 40 +++ 41 ++++ 42 +++ 43 +++ 44 ++++ COMPOUND NUMBER ACTIVITY S1Pi 129 + 130 ++ 131 ++ 132 ++ 133 ++ 134 ++ 135 + 136 + 137 + 138 + 139 + 140 + 141 ++ 142 ++ 143 ++ 144 ++ 145 + 146 ++ 147 ++ 148 ++ 149 ++ 150 ++ 151 + 152 + 153 + 154 +++ 155 ++ 156 +++ 157 +++ 158 ++++ Petition 870210054926, dated 06 / 18 / 2021, pp. 193 / 238 189 / 198 COMPOUND NUMBER ACTIVITY S1Pi 45 +++ 46 +++ 47 ++++ 48 ++++ 49 ++ 50 +++ 51 +++ 52 +++ 53 ++ 54 +++ 55 ++ 56 +++ 57 ++ 58 +++ 59 ++ 60 ++ 61 +++ 62 ++ 63 ++ 64 ++ 65 +++ 66 +++ 67 ++ 68 +++ 69 +++ 70 ++ 71 ++ 72 ++ 73 +++ 74 +++ COMPOUND NUMBER ACTIVITY S1Pi 159 +++ 160 ++++ 161 +++ 162 +++ 163 +++ 164 +++ 165 ++ 166 +++ 167 +++ 168 +++ 169 ++ 170 ++ 171 +++ 172 +++ 173 ++ 174 +++ 175 ++ 176 ++ 177 +++ 178 +++ 179 ++ 180 + 181 + 182 ++ 183 ++ 184 + 185 + 186 +++ 187 ++ 188 ++ Petition 870210054926, dated 06 / 18 / 2021, pp. 194 / 238 190 / 198 COMPOUND NUMBER ACTIVITY S1Pi 75 +++ 76 ++ 77 +++ 78 ++ 79 +++ 80 +++ 81 ++ 82 ++ 83 + 84 + 85 + 86 + 87 +++ 88 ++ 89 ++ 90 ++ 91 ++ 92 ++ 93 ++ 94 ++ 95 ++ 96 +++ 97 +++ 98 ++ 99 ++ 100 +++ 101 + 102 +++ 103 +++ 104 ++ COMPOUND NUMBER ACTIVITY S1Pi 189 + 190 ++ 191 + 192 + 193 + 194 ++ 195 ++ 196 ++ 197 ++ 198 +++ 199 +++ 200 +++ 201 +++ 202 ++ 203 ++ 204 ++ 205 ++ 206 +++ 207 ++ 208 ++ 209 ++ 210 ++ 211 ++ 212 + 213 ++ 214 ++ 215 ++ 216 ++ 217 + 218 + Petition 870210054926, dated 06 / 18 / 2021, pages 195 / 238 191 / 198 NUMBER OF THE COMPOUND ACTIVITY S1Pi 105 + 106 + 107 ++ 108 + 109 ++ 110 ++ 111 +++ 112 +++ 113 +++ 114 +++ COMPOUND NUMBER ACTIVITY S1Pi 219 +++ 220 +++ 221 +++ 222 + 223 ++ 224 + 225 + 226 ++ 227 + [000377] S1 Pi-S1 P5 data for specific compounds are presented in Table 3. Agonist values ​​(EC50) are reported in nM. Table 3 NUMBER OF COMPOUND S1Pi S1P2 S1P3 S1P4 S1P5 43 0.07 >10000 >10000 >10000 444 46 0.25 >10000 >10000 2171 194 47 0.03 >10000 >10000 >10000 22 56 0.32 >10000 >10000 >10000 139 58 0.29 >10000 >10000 >10000 47 166 0.14 8448 >10000 743 64 172 0.19 >10000 >10000 >10000 203 186 0.41 >10000 >10000 >10000 126 In Vivo Trials Determination of absolute oral bioavailability in rats. [000378] All pharmacokinetic studies were conducted in non-fasting female Sprague-Dawely rats (Simonsen Laboratories or Harlan Laboratories). The rats were housed in a Petition 870210054926, dated 06 / 18 / 2021, pages 196 / 238 192 / 198 The facility was authorized by ALAAC and the research was approved by the Institutional Animal Care and Use Committee (IACUC). The animals were acclimated to the laboratory for at least 48 hours before the start of the experiments. [000379] The compounds were formulated in 5% DMSO / 5% Tween20 and 90% purified water (intravenous infusion) or 5% DMSO / 5% Tween20 and 90% 0.1N HCl (oral gavage). Depending on the solubility properties of the compound, alternate oral formulations were used (e.g., 0.5% carboxymethylcellulose). The concentration of the dosing solutions was verified by HPLC-UV. For intravenous dosing, the compounds were administered via an infusion pump into the jugular vein over one minute in manually restrained animals (n=4 rats / compound). Oral dosing was performed by gavage using a standard stainless steel gavage needle (n=2-4 rats / compound). For both routes of administration, blood was collected at eight time points after dosing, with the final sample taken 24 h post-dose. Aliquots of blood and / or plasma samples were transferred to a 96-well polypropylene plate and frozen at -20°C until analysis. [000380] After thawing the blood and / or plasma samples at room temperature, 5 μL of DMSO were added to each well. Proteins were precipitated by adding 150 μL of acetonitrile containing 200 nM internal standard (4-hydroxy-3-(alpha-iminobenzyl)-1-methyl-6-phenylpyrindin-2-(1H)-one) and 0.1% formic acid. The plates were mixed for 1 min in a plate shaker to facilitate protein precipitation and then centrifuged at 3,000 rpm for 10 min to pelletize the protein. The supernatant was transferred to a transparent plate and centrifuged at 3,000 rpm for 10 min to pelletize any remaining solid material before LC / MS / MS analysis. Petition 870210054926, dated 06 / 18 / 2021, pages 197 / 238 193 / 198 Calibration curve standards were prepared by co-elution of 5 μL of compound stock in DMSO in freshly collected rat EDTA blood. An eight-point standard curve spanning a range of 5 nM to 10,000 nM was included with each bioanalytical series. The standards were processed identically to the rat pharmacokinetic samples. [000381] Concentrations in rat pharmacokinetic samples were determined using a standardized HPLC / MS / MS method relative to an eight-point standard curve. The system consisted of a Leap CTC Pal injector, an Agilent 1200 HPLC with a binary pump coupled to an Applied Biosystems 3200 QTrap. Compounds were chromatographed on a Phenomenex Synergy Fusion RP 20x2mm 2um Mercury Cartridge with Security Guard. A gradient method was used with mobile phase A consisting of 0.1% formic acid in water and mobile phase B consisting of 0.1% formic acid in acetonitrile at flow rates ranging from 0.7 to 0.8 mL / min. Ions were generated in positive ionization mode using an electrospray ionization (ESI) interface. Multiple reaction monitoring (MRM) methods were developed specifically for each compound. The heated nebulizer was set to 325°C with a nebulizer current of 4.8 μA.The collision energies used to generate secondary ions ranged between 29 and 39 V. Peak area ratios obtained from MRM of the specific mass transitions for each compound were used for quantification. The quantification limit of the method is typically 5 nM. Data were collected and analyzed using Analyst software version 1.4.2. [000382] Blood and / or plasma concentration versus time data were analyzed using non-behavioral methods (WinNonlin version 5.2; model 200 for oral dosing and model 202 for intravenous infusion). The absolute oral bioavailability (%) was Petition 870210054926, dated 06 / 18 / 2021, pages 198 / 238 194 / 198 calculated using the following expression: (Oral AUC χ IV Dose) / (IV AUC χ Oral Dose)x 100. Lymphopenia [000383] In mice: Female C57BL6 mice (Simonsen Laboratories, Gilroy, CA) were housed in an ALAAC-approved facility, and the research was approved by the Institutional Animal Care and Use Committee (IACUC). Animals were acclimated to the laboratory for at least 5 days h prior to the start of experiments. Mice (n=3 / compound / time point) were dosed by oral gavage with 1 mg / kg of compound formulated in a vehicle consisting of 5% DMSO / 5% Tween 20 and 90% 0.1N HCl. Control mice were dosed PO with the vehicle. Terminal whole blood samples were collected from isoflurane-anesthetized mice by cardiac puncture in EDTA. Whole blood was incubated with CD16 / CD32 from anti-mouse rats (Mouse BD Fc Block, #553141), CD45R / B220 PE from anti-mouse rats (BD #553089), CD8a from anti-mouse rats APC-Cy7 (BD #557654), and CD4 Alexa Fluor647 from anti-mouse rats (BD #557681) for 30 min on ice.Red blood cells were lysed using BD Pharm Lyse Buffer (#555899) and white blood cells were analyzed by FACS. Lymphopenia was expressed as the percentage of white blood cells that were CD4 or CD8 positive T cells. The total lymphopenia response over 24 h was estimated by calculating the area under the effect curve (AUEC) using the linear trapezoidal rule. [000384] In rats: Female rats (Simonsen Laboratories, Gilroy, CA) were housed in an ALAAC-approved facility, and the research was approved by the Institutional Animal Care and Use Committee (IACUC). The animals were acclimated to the laboratory for at least 5 days prior to the start of the experiments. Rats (n=3 / compound / time point) were dosed by oral gavage with 1 Petition 870210054926, dated 06 / 18 / 2021, pages 199 / 238 195 / 198 mg / kg of compound formulated in a vehicle consisting of 5% DMSO / 5% Tween 20 and 90% 0.1N HCl. Control rats were measured PO2 with the vehicle. Whole blood was collected from isoflurane-anesthetized rats via the retroorbital venous plexus, and terminal whole blood samples were collected by cardiac puncture in EDTA. Whole blood was incubated with anti-mouse CD32 (BD #550271), anti-mouse CD45R / B220 PE (BD #554881), anti-mouse CD4 PECy5 (BD #554839), and anti-mouse CD8a APC (eBioscience #17-0084) for 30 minutes on ice. Red blood cells were lysed using BD Pharm Lyse Buffer (#555899) and white blood cells were analyzed with a BD FACSArray. Lymphopenia was expressed as the percentage of white blood cells that were CD4 or CD8 positive T cells. The total lymphopenia response at 24 h was estimated by calculating the area under the effect curve (AUEC) using the linear trapezoidal rule.In some experiments, total lymphocyte counts were determined using an impedance-based veterinary hematology analyzer (IDEXX Preclinical Research Services, Sacramento, CA). [000385] Rat lymphopenia data for specific compounds are presented in Table 4. The percentage of lymphopenia 24 h after a single dose regimen of 0.2 mg / kg is reported. The estimated dose required to produce 50% lymphopenia (ED50) 24 h after a 3- to 5-day dosing regimen is also reported. N / A is not available. Table 4 Compound Number % of Lymphopenia after 24 h (0.2 mg / kg) ED50 (mg / kg) 43 40 N / A 46 39 N / A 47 17 N / A Petition 870210054926, dated 06 / 18 / 2021, pages 200 / 238 196 / 198 Compound Number % of Lymphopenia after 24 h (0.2 mg / kg) ED50 (mg / kg) 56 52 N / A 58 49 N / A 166 47 0.07 172 22 0.20 186 25 0.20 Evaluation of the Therapeutic Index in Rats [000386] Studies can be conducted on non-fasting male and female Sprague-Dawely rats (Simonsen Laboratories). Rats can be housed in an ALAAC-approved facility and the research has been approved by the Institutional Animal Care and Use Committee (IACUC). Animals were acclimated to the laboratory for at least 5 days prior to the start of experiments. [000387] The compounds can be formulated as suspensions in a vehicle consisting of 0.5% carboxymethyl cellulose (Acros Organics) in purified water (pH adjusted to ~2.2 with hydrochloric acid). The same formulation is used in the rat lymphopenia and toxicological studies described below. The concentration of each compound in suspension should be verified to be within ± 10% of the target concentration by HPLC-UV. [000388] Before conducting toxicological studies, the effect of three to five daily doses of each compound on peripheral T-cell counts in female rats can be determined (see lymphopenia measurements in rats above). In these lymphopenia studies, blood samples were collected in EDTA at intervals after the final study dose. Collection times do not need to be identical for each study; however, all studies may include a sample collected 24 hours after the final dose. Lymphopenia data were Petition 870210054926, dated 06 / 18 / 2021, pages 201 / 238 197 / 198 used as a biomarker to equally select pharmacologically active doses for the subsequent toxicology study. The low dose for the toxicology study is the dose of each compound that resulted in a 50% reduction in T-cell count 24 h after the final dose in the lymphopenia study relative to vehicle-treated rats. [000389] In toxicology studies, three male and three female rats per group are assigned to dosage groups using randomization based on body weight. A control group in each study receives the vehicle. All animals are orally dosed by gavage on 5 or 14 consecutive days at a dose volume of 5 mL / kg / day. Animals are observed daily for any manifestations of adverse effects. Twenty-four hours after the final study dose, rats are anesthetized with isoflurane and a terminal blood sample is collected by intracardiac puncture for hematology and clinical chemistry evaluation (IDEXX Laboratories, Sacramento, CA). Lungs with trachea are collected, weighed, and then prepared for histology by perfusion with 10% neutral buffered formalin through the trachea. Internally fixed lungs are then preserved in 10% neutral buffered formalin and submitted for histological examination (IDEXX). [000390] The dose of each compound that results in a 10% increase in lung to terminal body weight ratio can be estimated for each compound by linear interpolation. The therapeutic index can then be estimated as the ratio of the dose that produces a 10% increase in lung weight to the dose that produces 50% T-cell depletion. Description of the TNBS Crohn's Colitis Model in Rats [000391] Male Sprague-Dawley rats (180-200 g) are acclimatized for seven days and then assigned to groups of 8 rats. Petition 870210054926, dated 06 / 18 / 2021, pages 202 / 238 198 / 198 so that each group has approximately the same average weight. Twenty-four hours before the onset of the disease, the rats are deprived of food. The rats are anesthetized and weighed, then 80 mg / kg of TNBS solution (50% TNBS: 50% anhydrous ethanol) is instilled into the colon through a 20g feeding needle inserted into the anus. The rats are kept in a head-down position until recovery from anesthesia. Daily oral dosing is initiated 2 h after TNBS instillation for six days. Prednisolone serves as a positive control and is administered orally daily at 10 mg / kg. Body weights are monitored daily and 24 h after the last dose, all groups are terminated. The colon is removed, free of fecal matter, and examined for abrupt changes including strictures, adhesions, and ulcers. Colon length, weight of the distal 2 cm, and wall thickness were recorded. Description of an Influenza A H1N1 Model in Mice [000392] Male C57Bl / 6 mice (6 to 8 weeks old) can be acclimatized for seven days and then assigned to groups of 5 to 8 mice so that each group has approximately the same average weight. Mice can be infected with the mouse-adapted influenza A virus 104PFUs (A / WSN / 33) via the intratracheal route. Mice can then be treated with 0.2 to 1.5 mg / kg of compound 1 hour after infection. Forty-eight hours after infection, mice can be euthanized by cervical dislocation and bronchoalveolar lavage fluid can be collected. Quantitative cytokine analysis can be performed by ELISA. In some experiments, whole-body perfusion can be performed and lungs can be collected for cellular enumeration of inflammatory cells. Longevity studies can be performed by infecting mice with an influenza A virus adapted to 3-10x104 PFUs for 14 days.

Claims

1. Compound, characterized in that it has Formula (I), or a pharmaceutically acceptable salt or tautomer thereof: wherein a dashed line signifies that a single bond or a double bond may be present, provided that there are two double bonds and three single bonds in the ring comprising A1, A2, and A3; each A1, A2, and A3 is independently CH or S or N; provided that one of A1, A2, and A3 is S; R1 is Y, R3 is C2-4 alkyl; and Y is -CN, -Cl, -I, R2 is -O-R3, -COOH, -COOR3 or -CF3; OR A / OR Petition 870210054926, dated 18 / 06 / 2021, p. 204 / 238 2 / 29 X is -NR'R or -OR'; R' is H, C1-4 alkyl, n-hydroxy C1-4 alkyl, -SO2-R3, or -CO-R3; R is H, -SO2-R5, C1-4 alkyl optionally substituted by 1 or more R4, or a ring portion optionally substituted by R6, and such ring portion is piperidinyl, cyclohexyl, morpholinyl, thiazolyl, pyrazolyl, pyrrolidinyl, imidazolyl, or phenyl;R' is H, C1-4 alkyl, or -CO-R3, each R4 is independently H, halo, OH, oxo, =NH, NH2, -COOH, F, -NHR3, -N(R7R7),-SO2-R3, -SO2-N(R7R7), -N(R3)-SO2-R3, -COOR3, -OCO-R3, -CO-N(R7R7), -N(R3)-COR3, C1-3 alkyl, C1-3 alkoxy, and a ring portion optionally substituted for R6, such ring portion being piperazinyl, piperidinyl, morpholinyl, pyrrolidinyl, pyrazolyl, imidazolyl, benzimidazolyl, azetidinyl, cyclobutynyl, or phenyl; each R5 is independently R4, C1-4 alkyl, C3-6 cycloalkyl, or C1-4 alkyl optionally substituted by 1 or more R4; each R6 is independently halo, OH, -NH2, -NHR3, N(R3R3), -COOH, -COOR3, -NHCO-R3;each R7 is independently C1-4 alkyl or H, or two R7 taken together at the nitrogen atom to which they are attached form a saturated heterocyclic ring with 4, 5, or 6 members containing 0 or 1 additional heteroatoms, where such additional heteroatom is O or N, wherein the heterocycle is optionally substituted by -OH, -NH2, -N(R3R3), n-hydroxy C1-4 alkyl, -(CH2)m-COOH, -(CH2)m-COOR3; each m is independently 0, 1, 2, or 3; wherein the structure of Formula (I) is selected from the group Petition 870210054926, dated 18 / 06 / 2021, page. 205 / 238 3 / 29 consisting of the Formulas ai to ax: ai a-ii a-iii a-iv av a-vi a-vii a-viii a-ix ax; 2. Compound according to claim 1, characterized in that: R1 is Y, R3 is C2-4 alkyl; and Y is -CN, -Cl, I, -O-R3 or -CF3.

3. Compound according to claim 2, characterized in that R3 is isopropyl or ethyl.

4. Compound according to claim 2, characterized in that Y is -CN or -O-C2H5.

5. Compound, according to claim 1, characterized in that R2 is: Petition 870210054926, dated 06 / 18 / 2021, page 206 / 238 4 / 29 6. Compound according to claim 1, characterized in that R2 is:

7. Compound according to claim 5, characterized in that R2 is:

8. Compound according to claim 5, characterized in that R2 is:

9. Compound, according to claim 6, characterized in that R2 is: Petition 870210054926, dated 06 / 18 / 2021, page 207 / 238 5 / 29 10. Compound according to claim 6, characterized in that R2 is:

11. Compound according to claim 1, characterized in that it has an enantiomeric purity of at least 90%.

12. Compound according to claim 1, characterized in that it has an EC50 as an agonist of a mutant S1P receptor of subtype 1 that has a unique mutation with respect to the wild-type S1P receptor of subtype 1 such that the 101st amino acid residue is changed from asparagine to alanine.

13. Compound according to claim 12, characterized in that it has an EC50 as an agonist of S1P receptor subtype 1 that is at least twenty times lower than its EC50 as an agonist of a mutant form of S1P receptor subtype 1 that has a single mutation with respect to the wild-type S1P receptor subtype 1 such that the 101st amino acid residue is changed from asparagine to alanine.

14. Compound, according to claim 1, characterized in that it has a therapeutic index of at least 5 as measured in rats following 5 or 14 days of dosing with the compound, wherein the therapeutic index is the ratio of the dose achieving a less than or equal to 10% increase in body weight between lungs and terminal at the conclusion of those 5 or 14 days and the dose achieving 50% lymphopenia. Petition 870210054926, dated 06 / 18 / 2021, pp. 208 / 238 6 / 29 15. Compound according to claim 14, characterized in that the therapeutic index is at least 10.

16. Compound according to claim 14, characterized in that the therapeutic index is at least 20.

17. Compound according to claim 14, characterized in that the therapeutic index for the compound is greater than the therapeutic index for the enantiomer of the compound.

18. Compound according to claim 17, characterized in that the therapeutic index for the compound is at least 150% of the therapeutic index for the enantiomer of the compound.

19. Compound according to claim 2, characterized in that Y is Cl.

20. Compound according to claim 2, characterized in that Y is CF3.

21. Compound according to claim 2, characterized in that Y is CN.

22. Compound according to claim 1, characterized in that X is -NR'R.

23. Compound according to claim 1, characterized in that X is -OR'.

24. Compound according to claim 23, characterized in that X is -OH.

25. Compound according to claim 23, characterized in that X is -OCO-R3.

26. Compound according to claim 25, characterized in that R3 is C1-3 alkyl.

27. Compound according to claim 22, characterized in that R' is H.

28. Compound according to claim 22, characterized in that R' is -COR3. Petition 870210054926, dated 06 / 18 / 2021, pp. 209 / 238 7 / 29 29. Compound according to claim 22, characterized in that R' is -SO2-R3.

30. Compound according to claim 22, characterized in that R is H.

31. Compound according to claim 22, characterized in that R is -SO2-R5.

32. Compound according to claim 22, characterized in that R is a C1-4 alkyl optionally substituted by one or more R4s.

33. Compound according to claim 22, characterized in that R is -(CRaRb)n-R4; each Ra and each Rb is independently selected from the group consisting of H, hydroxyl and methyl or Ra and Rb bonded to the same carbon atom taken together are oxo; en is 0, 1, 2, or 3.

34. Compound according to claim 33, characterized in that n is 2.

35. Compound according to claim 34, characterized in that R4 is -OH, -NH2, -NHR3, -N(R7R7), or -COOH.

36. Compound according to claim 31, characterized in that R5 is a C1-4 alkyl optionally substituted by one or more R4s.

37. Compound according to claim 2, characterized in that Y is CN.

38. Compound according to claim 36, characterized in that R5 is -C2H5-N((R7R7) or -CH2-CO-N(R7R7).

39. Compound according to claim 37, characterized in that R5 is C2H5-O-R3.

40. Compound according to claim 22, characterized in that X is -NH-CO-N(R7R7).

41. Compound, according to claim 1, characterized by the fact that it is selected from: Petition 870210054926, dated 06 / 18 / 2021, p. 210 / 238 8 / 29 213 / 238 11 / 29 ЗН^ ß ^s=o Petition 870210054926, dated 06 / 18 / 2021, p. 214 / 238 12 / 29 II ß ν-ν Petition 870210054926, dated 06 / 18 / 2021, p. 215 / 238 13 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 216 / 238 14 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 217 / 238 15 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 218 / 238 16 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 219 / 238 17 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 220 / 238 18 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 221 / 238 19 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 222 / 238 20 / 29 Petition 870210054926, dated 06 / 18 / 2021, p. 223 / 238 21 / 29 Petition 870210054926, dated 06 / 18 / 2021, p.224 / 238 22 / 29 Petition 870210054926, dated 06 / 18 / 2021, pg. 225 / 238 23 / 29 Petition 870210054926, dated 06 / 18 / 2021, pg. 226 / 238 24 / 29 Petition 870210054926, dated 06 / 18 / 2021, pg. 227 / 238 25 / 29 Petition 870210054926, dated 06 / 18 / 2021, pg. 228 / 238 26 / 29 Petition 870210054926, dated 06 / 18 / 2021, pg. 229 / 238 27 / 29 Petition 870210054926, dated 06 / 18 / 2021, pp. 230 / 238 28 / 29 or any pharmaceutically acceptable salt or tautomer thereof.

42. Compound according to claim 41, characterized in that it is selected from: or any pharmaceutically acceptable salt or tautomer thereof.

43. Pharmaceutical composition, characterized in that it comprises a compound, as defined in any one of claims 1 to 42, and a suitable excipient.

44. Pharmaceutical composition, characterized in that it comprises the compound as defined in any one of claims 1 to 42 and a second medicament.

45. Composition, according to claim 44, characterized in that the second medicinal product is medically indicated for the treatment of multiple sclerosis, transplant rejection, or acute respiratory distress syndrome. Petition 870210054926, dated 06 / 18 / 2021, pp. 231 / 238 29 / 29 46. ​​Use of a compound, as defined in any one of claims 1 to 42, characterized in that it is for the manufacture of a medicament for the treatment of a disease in a patient in which activation or agonism of a sphingosine 1-phosphate receptor of subtype 1 is medically indicated, the disease being selected from multiple sclerosis, transplant rejection, acute respiratory distress syndrome, ulcerative colitis, influenza, Crohn's disease or adult respiratory distress syndrome.

47. Use according to claim 46, characterized in that the active compound acts as an agonist of the sphingosine-1-phosphate receptor subtype 1 to a greater extent than the active compound acts as an agonist of a sphingosine-1-phosphate receptor subtype 3.

48. Use according to claim 46, characterized in that the sphingosine-1-phosphate receptor of subtype 1 is disposed in a living mammal.