GANCIA EMANUELA (US)
KNIGHT JAMIE (US)
HYND GEORGE (US)
JACKSON PHILIP (US)
JENNINGS NEIL (US)
BULL RICHARD (US)
MILLER THOMAS ALLEN (US)
LEVENSON JONATHAN MAX (US)
MARTENS LAUREN (US)
LARSON KELLEY CRONIN (US)
BRUHN SUZANNE (US)
TATE BARBARA (US)
CRIDLAND ANDREW (US)
GANCIA EMANUELA (US)
KNIGHT JAMIE (US)
HYND GEORGE (US)
JACKSON PHILIP (US)
JENNINGS NEIL (US)
BULL RICHARD (US)
| WO2015187827A1 | 2015-12-10 | |||
| WO2013033068A1 | 2013-03-07 |
| EP2848615A1 | 2015-03-18 |
MIGUEL GUERRERO; MARIANGELA URBANO; SUBASH VELAPARTHI; JIAN ZHAO; MARIE-THERESE SCHAEFFER; STEVEN BROWN; HUGH ROSEN; EDWARD ROBERT: "Discovery, design and synthesis of the first reported potent and selective sphingosine-1-phosphate 4 (S1P) receptor antagonists", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, ELSEVIER, AMSTERDAM NL, vol. 21, no. 12, 21 April 2011 (2011-04-21), Amsterdam NL , pages 3632 - 3636, XP028387816, ISSN: 0960-894X, DOI: 10.1016/j.bmcl.2011.04.097
DATABASE Registry CAS; 25 June 2019 (2019-06-25), ANONYMOUS : "Benzamide, 3-(4-methyl2-thiazolyl)-N-(2,4,6- trichlorophenyl)-", XP093073654, retrieved from STN Database accession no. 2345483-51-2
DATABASE Registry CAS; 2 September 2020 (2020-09-02), ANONYMOUS : "4-Pyrimidinecarboxamid e, 2-(1-piperidinyl)-N -(2,4,6-trifluorophen yl)-", XP093073656, retrieved from STN Database accession no. 2470619-02-2
| CLAIMS What is claimed is: 1. A compound of Formula X: or a pharmaceutically acceptable salt thereof, wherein ring A is a 5-6 membered aryl, 5-10 membered heteroaryl or 3-10 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, and wherein each -C1-C6 alkyl and -C1-C6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, - C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; ring B is a 5-6 membered aryl, a 5-10 membered heteroaryl or 3-10 membered heterocyclyl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, and wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, - N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; L1 is -C(O)N(Re)-, -N(Re)C(O)-, -S(O)2N(H)-, -N(H)S(O)2-, -N(Re)C(Rf)2-, or -C(Rf)2N(Re)-, wherein the connectivity of L1, from left to right, is with respect to the representation of Formula (X); ring C is a 5-6 membered aryl or 5-6 membered heteroaryl containing 1-4 heteroatoms each selected from the group consisting of N, O, and S, wherein ring C is optionally substituted with one or more independent occurrences of H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, - C(O)N(Rb)2, -N(Rb)C(O)Rc, -N(Rb)S(O)2Rd, or and each occurrence of R7 is independently H, halo, -OH, -C1-C6 alkoxy, -N(Rb)2, C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd, or 3-10 membered heterocyclyl optionally substituted with oxo, or two R7 are joined together to form oxo, and wherein each occurrence of R8 is H, halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, and -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; each occurrence of Ra, Rb, or Re is independently H or -C1-C6 alkyl, wherein - C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo or -OH, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc and Rf is independently H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is independently -C1-C6 alkyl or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 2. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: R1 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, - N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R2 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, - N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; each of R4 and R5 is independently halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1- 6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; each of R6, R19, and R20 is independently H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein one of R6, R19, and R20 is not H, and wherein -C1-C6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc or -N(Rb)S(O)2Rd, and -C1- 6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc or -N(Rb)S(O)2Rd; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen- containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, - C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1- C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; L1 is -C(O)N(Re)-, -N(Re)C(O)-, -S(O)2N(H)-, -N(H)S(O)2-, -N(Re)C(Rf)2-, or -C(Rf)2N(Re)-, wherein the connectivity of L1, from left to right, is with respect to the representation of Formula I; each occurrence of Ra, Rb, and Re is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo or -OH, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc and Rf is independently H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is -C1-C6 alkyl or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 3. A compound of Formula II: or a pharmaceutically acceptable salt thereof, wherein R1 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R2 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R3 is H or -C1-C6 alkyl; each of R4 and R5 is independently halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1- 6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R6 is -C1-C6 alkyl or -C(O)-N(Ra)2, wherein -C1-C6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, - C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd, and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen- containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, - C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1- C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; each occurrence of Ra and Rb is independently H or -C1-C6 alkyl, wherein -C1- C6 alkyl is optionally substituted with one or more independent occurrences of halo or -OH, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc is H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1- C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is independently -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 4. The compound of claim 1 or 3, wherein the compound is a compound of Formula II-a: 5. The compound of any one of claims 1-4, wherein the compound is a compound of Formula II-b: 6. The compound of any one of claims 1-4, wherein R6 is wherein each occurrence of R7 is independently H, halo, -OH, -C1-C6 alkoxy, -N(Rb)2, C(O)N(Rb)2, and -N(Rb)C(O)Rc, -N(Rb)S(O)2Rd, or 3-10 membered heterocyclyl optionally substituted with oxo, or two R7 are joined together to form oxo; and R8 is H, halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, and -N(Rb)C(O)Rc, or - N(Rb)S(O)2Rd. 7. The compound of any one of claims 1-6, wherein each of R1 and R2 is independently chloro, bromo, iodo, fluoro, -CN, -C1-C6 alkyl, or -C1-C6 alkoxy. 8. The compound of any one of claims 1-7, wherein R1 and R2 are chloro. 9. The compound of any one of claims 1-8, wherein ring B is 10. The compound of any one of claims 1-9, wherein ring B is , 11. The compound of any one of claims 1-10, wherein ring B is , , 12. The compound of any one of claims 1-11, wherein ring B is 13. The compound of any one of claims 1-12, wherein R6 is 14. The compound of any one of claims 1-13, wherein R6 is 15. The compound of any one of claims 1-14, wherein R6 is 16. A compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein R1 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R2 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R3 is H or -C1-C6 alkyl; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen- containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, - C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, and wherein each -C1-C6 alkyl and -C1- C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd; ring C is a nitrogen-containing 5-6 membered heteroaryl optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, - C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd; each occurrence of Ra, Rb, and Re is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc is independently H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is -C1-C6 alkyl or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 17. The compound of claim 16, wherein the compound is a compound of Formula III-a, Formula III-b, or Formula III-c: wherein each of R9, R10, R11, and R12 is independently H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, and -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)2C(O)Rc, and -N(Rb)S(O)2Rd. 18. The compound of claim 15 or 16, wherein each of R9, R10, R11, and R12 is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, - C(O)N(Rb)2, or -N(Rb)2C(O)Rc, and -N(Rb)S(O)2Rd. 19. The compound of claim 16-18, wherein the compound is a compound Formula III-d or Formula III-e: wherein each of R17 and R18 is independently H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, and -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)2C(O)Rc, and -N(Rb)S(O)2Rd; and Rx is H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, and -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, or -N(Rb)2C(O)Rc, and -N(Rb)S(O)2Rd. 20. The compound of any one of claims 16-19, wherein ring B is . 21. A compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein ring A is a sulfur-containing 5-10 membered heteroaryl, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, - C1-C6 alkyl, -C1-6 alkoxy, and -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R3 is H or -C1-C6 alkyl; each of R4 and R5 is independently halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R6 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein -C1-C6 alkyl is substituted with one or more independent occurrences of halo, -OH, - C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, and -N(Rb)S(O)2Rd, and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd; each occurrence of Ra and Rb is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc is H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is independently -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each - C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 22. A compound of Formula IV-A: or a pharmaceutically acceptable salt thereof, wherein each of R15, R16, and R17 is independently H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, - C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R3 is H or -C1-C6 alkyl; each of R4 and R5 is independently halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R6 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein -C1-C6 alkyl is substituted with one or more independent occurrences of halo, -OH, - C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, and -N(Rb)S(O)2Rd, and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, and -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd; each occurrence of Ra and Rb is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc is H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is independently -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each - C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 23. The compound of claim 21 or 22, wherein the ring B is . 24. The compound of any one of claims 21-23, wherein R15, R16, and R17 are H. 25. The compound of any one of claims 21-24, wherein R3 is H. 26. The compound of any one of claims 21-25, wherein R4 and R5 are unsubstituted -C1- C6 alkyl. 27. The compound of any one of claims 21-26, wherein R4 and R5 are unsubstituted methyl. 28. The compound of any one of claims 21-27, wherein R6 is methyl substituted with hydroxyl. 29. A compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein R3 is H or -C1-C6 alkyl; each of R4 and R5 is independently halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R6 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein -C1-C6 alkyl is substituted with one or more independent occurrences of halo, -OH, - C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, and -N(Rb)S(O)2Rd, and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; ring E is a nitrogen-linked 3-10 membered heterocyclyl optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1- C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd;. ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd; each occurrence of Ra and Rb is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc is H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is independently -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each - C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 30. The compound of claim 29, wherein ring B is . 31. The compound of claim 29 or 30, wherein ring E is N-linked piperidinyl. 32. The compound of any one of claims 29-31, wherein ring E is N-linked pyrrolidinyl. 33. The compound of any one of claims 29-32, wherein R3 is H. 34. The compound of any one of claims 29-33, wherein R4 and R5 are unsubstituted -C1- C6 alkyl. 35. The compound of any one of claims 29-34, wherein R4 and R5 are unsubstituted methyl. 36. The compound of any one of claims 29-35, wherein R6 is methyl substituted with hydroxyl. 37. A compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein each of R1, R2, R9, R10, and R11 is independently H, halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R3 is H or -C1-C6 alkyl; each of R4 and R5 is independently halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; R6 is halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein -C1-C6 alkyl is substituted with one or more independent occurrences of halo, -OH, - C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, and -N(Rb)S(O)2Rd, and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C1-C6 alkoxy, -N(Rb)2, -C(O)N(Rb)2, -N(Rb)C(O)Rc, or -N(Rb)S(O)2Rd; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(Ra)2, -C1-C6 alkyl, -C1-C6 alkoxy, or -C(O)-N(Ra)2, wherein each -C1-C6 alkyl and -C1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C1-C6 alkoxy, - N(Rb)2, -C(O)N(Rb)2, -N(Rb)2C(O)Rc, or -N(Rb)S(O)2Rd; X is a bond or oxygen; each occurrence of Ra and Rb is independently H or -C1-C6 alkyl, wherein -C1-C6 alkyl is optionally substituted with one or more independent occurrences of halo, or two Ra are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl, or two Rb are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C1-C6 alkyl; each occurrence of Rc is H, -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each -C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of Rd is independently -C1-C6 alkyl, or -C1-C6 alkoxy, wherein each - C1-C6 alkyl and -C1-C6 alkoxy is optionally substituted with one or more independent occurrences of halo. 38. The compound of claim 37, wherein ring B is . 39. The compound of claim 37 or 38, wherein R3 is H. 40. The compound of any one of claims 37-39, wherein R4 and R5 are unsubstituted -C1- C6 alkyl. 41. The compound of any one of claims 37-40, wherein R4 and R5 are unsubstituted methyl. 42. The compound of any one of claims 37-41, wherein R6 is methyl substituted with hydroxyl. 43. The compound of any one of claims 37-42, wherein R1 is H. 44. The compound of any one of claims 37-43, wherein R9 is H, chloro, fluoro, or -C1-C6 alkyl, wherein the -C1-C6 alkyl can be optionally substituted with one or more independent occurrences of halo. 45. The compound of any one of claims 37-44, wherein R10 is H, -C1-C6 alkyl, fluoro, or chloro. 46. The compound of any one of claims 37-45, wherein R2 is H, fluoro, or -C1-C6 alkyl. 47. The compound of any one of claims 37-46, wherein R11 is H, chloro, fluoro, -C1-C6 alkoxy, or -C1-C6 alkyl, wherein the , -C1-C6 alkoxy and -C1-C6 alkyl can be optionally substituted with one or more independent occurrences of halo. 48. A compound of the formula: or a pharmaceutically acceptable salt thereof. 49. A pharmaceutical composition comprising a compound of any one of claims 1-48 and a pharmaceutically acceptable excipient. 50. A method of treating a neurological disorder, a cognitive disorder, or neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound of any one of claims 1-48. 51. A method of treating Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Huntington's disease, lysosomal storage diseases including Gaucher, spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, SCA6, SCAT, and SCA17), spinobulbar muscular atrophy (SBMA) or Kennedy disease, dentatorubropallidoluysian atrophy (DRPLA), ALS, AIDS dementia, frontotemporal dementia, corticobasal ganglionic degeneration, progressive supranuclear palsy, Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia, corticobasal ganglionic degeneration, hereditary spastic paraplegia, multiple sclerosis, neuromyelitis optica (Devic’s disease), concentric sclerosis (Baló’s disease), encephalomyelitis including acute disseminated encephalomyelitis (ADEM), acute haemorrhagic leucoencephalitis (AHL), Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Schilder’s disease, fibromyalgia, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve (e.g. in Bell's palsy) and post radiation injury; demyelination due to hypoxic- ischaemic events such as stroke, acute ischemic optic neuropathy, or other ischemia, and carbon monoxide exposure; demyelination due to metabolic disruption such as central pontine myelolysis (CPM) or extrapontine myelinolysis (EPM); demyelination due to inherited conditions such as Charcot-Marie-Tooth disease (CMT), Sjogren- Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, Friedreich's ataxia, Pelizaeus-Merzbacher disease, Bassen-Kornzweig syndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy, Leber’s optic neuropathy, and nerve damage due to pernicious anemia; demyelination due to a viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, tabes dorsalis due to untreated syphilis, HIV, or subacute sclerosing panencephalitis due to measles virus; demyelination due to toxic exposure such as chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease), chemotherapy, mitochondrial toxins such as cyanide or hydrogen sulphide, or exposure to chemicals such as organophosphates; demyelination due to a dietary deficiency such as vitamin B12 deficiency, vitamin E deficiency and copper deficiency; or demyelination which has unknown causes or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease, and Bell's palsy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-48. 52. A method of treating a neurological disorder, a cognitive disorder, or neurodegenerative disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 49. 53. A method of treating Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Huntington's disease, spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, SCA6, SCAT, and SCA17), spinobulbar muscular atrophy (SBMA) or Kennedy disease, dentatorubropallidoluysian atrophy (DRPLA), ALS, AIDS dementia, frontotemporal dementia, corticobasal ganglionic degeneration, progressive supranuclear palsy, Creutzfeldt-Jakob disease, Gerstmann-Sträussler- Scheinker syndrome, fatal familial insomnia, corticobasal ganglionic degeneration, hereditary spastic paraplegia, multiple sclerosis, neuromyelitis optica (Devic’s disease), concentric sclerosis (Baló’s disease), encephalomyelitis including acute disseminated encephalomyelitis (ADEM), acute haemorrhagic leucoencephalitis (AHL), Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Schilder’s disease, fibromyalgia, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve (e.g. in Bell's palsy) and post radiation injury; demyelination due to hypoxic-ischaemic events such as stroke, acute ischemic optic neuropathy, or other ischemia, and carbon monoxide exposure; demyelination due to metabolic disruption such as central pontine myelolysis (CPM) or extrapontine myelinolysis (EPM); demyelination due to inherited conditions such as Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, Friedreich's ataxia, Pelizaeus-Merzbacher disease, Bassen-Kornzweig syndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy, Leber’s optic neuropathy, and nerve damage due to pernicious anemia; demyelination due to a viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, tabes dorsalis due to untreated syphilis, HIV, or subacute sclerosing panencephalitis due to measles virus; demyelination due to toxic exposure such as chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease), chemotherapy, mitochondrial toxins such as cyanide or hydrogen sulphide, or exposure to chemicals such as organophosphates; demyelination due to a dietary deficiency such as vitamin B12 deficiency, vitamin E deficiency and copper deficiency; or demyelination which has unknown causes or multiple causes such as trigeminal neuralgia, Marchiafava- Bignami disease, and Bell's palsy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 48. 54. A method of treating lysosomal storage disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of compound of any one of claims 1-48. 55. A method of treating Activator deficiency, Alpha-mannosidosis, AB variant, Aspartylglucosaminuria, Batten–Spielmeyer–Vogt disease, Beta-galactosidase / GM1 gangliosidosis, Beta-mannosidosis, Chronic hexosaminidase A deficiency, cystinosis, CLN7 disease, Congenital cathepsin D deficiency, Cholesteryl ester storage disease, Cystinosis, Danon disease, Fabry disease, fucosidosis, I-cell disease, Krabbe disease, Farber disease, Finnish Variant, gangliosidosis, galactosialidosis, Gaucher disease (including type I, type II, and type III), GM2-AP deficiency, glycoprotein storage disorders, glucocerebroside, glycogen storage disease type II (pompe disease), GM2 gangliosidosis, German/Serbian late infantile, Hunter syndrome, Hurler syndrome, Hurler–Scheie syndrome, hyaluronidase deficiency, Infantile free sialic acid storage disease, Jansky–Bielschowsky disease, Juvenile hexosaminidase A deficiency, Late infantile variant, leukodystrophies, Kufs disease, lysosomal acid lipase deficiency, Maroteaux–Lamy syndrome, Metachromatic leukodystrophy, metachromatic leukodystrophy, Morquio syndrome, multiple sulfatase deficiency, multiple sulfatase deficiency, mucopolysaccharidoses, Mucolipidosis Type I (sialidosis), Mucolipidosis Type II (I-cell disease), Mucolipidosis Type III (pseudo-Hurler polydystrophy/phosphotransferase deficiency), Mucolipidosis Type IV (mucolipidin 1 deficiency), Niemann–Pick diseases, Neuronal ceroid lipofuscinoses, Northern epilepsy, Pycnodysostosis, Pompe disease, Salla disease, SAP deficiency, Sandhoff disease, saposin B deficiency, Sanfilippo syndrome, Santavuori–Haltia disease, Scheie syndrome, Schindler disease, Sly syndrome, Sphingolipidoses, sulfatidosis, Tay–Sachs disease, Turkish late infantile, variant AB, and Wolman disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1-48. 56. A method of treating lysosomal storage disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 49. 57. A method of treating Activator deficiency, Alpha-mannosidosis, AB variant, Aspartylglucosaminuria, Batten-Spielmeyer-Vogt disease, Beta-galactosidase / GM1 gangliosidosis, Beta-mannosidosis, Chronic hexosaminidase A deficiency, cystinosis, CLN7 disease, Congenital cathepsin D deficiency, Cholesteryl ester storage disease, Cystinosis, Danon disease, Fabry disease, fucosidosis, I-cell disease, Krabbe disease, Farber disease, Finnish Variant, gangliosidosis, galactosialidosis, Gaucher disease (including type I, type II, and type III), GM2-AP deficiency, glycoprotein storage disorders, glucocerebroside, glycogen storage disease type II (pompe disease), GM2 gangliosidosis, German/Serbian late infantile, Hunter syndrome, Hurler syndrome, Hurler-Scheie syndrome, hyaluronidase deficiency, Infantile free sialic acid storage disease, Jansky-Bielschowsky disease, Juvenile hexosaminidase A deficiency, Late infantile variant, leukodystrophies, Kufs disease, lysosomal acid lipase deficiency, Maroteaux-Lamy syndrome, Metachromatic leukodystrophy, metachromatic leukodystrophy, Morquio syndrome, multiple sulfatase deficiency, multiple sulfatase deficiency, mucopolysaccharidoses, Mucolipidosis Type I (sialidosis), Mucolipidosis Type II (I-cell disease), Mucolipidosis Type III (pseudo-Hurler polydystrophy/phosphotransferase deficiency), Mucolipidosis Type IV (mucolipidin 1 deficiency), Niemann-Pick diseases, Neuronal ceroid lipofuscinoses, Northern epilepsy, Pycnodysostosis, Pompe disease, Salla disease, SAP deficiency, Sandhoff disease, saposin B deficiency, Sanfilippo syndrome, Santavuori-Haltia disease, Scheie syndrome, Schindler disease, Sly syndrome, Sphingolipidoses, sulfatidosis, Tay-Sachs disease, Turkish late infantile, variant AB, and Wolman disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 49. |
[00034] In an aspect, described herein is a compound of Formula III: or a pharmaceutically acceptable salt thereof, wherein R 1 is halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 2 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or - N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 3 is H or -C 1 -C 6 alkyl; ring B is a nitrogen- containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or - C(O)-N(R a ) 2 , and wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, - N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , or -N(R b )S(O) 2 R d ; ring C is a nitrogen- containing 5-6 membered heteroaryl optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or -N(R b )S(O) 2 R d ; each occurrence of R a , R b , and R e is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, or two R a are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl, or two R b are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl; each occurrence of R c is independently H, -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of R d is -C 1 -C 6 alkyl or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo. [00035] In some embodiments, the compound is a compound of Formula III-a, Formula III-b, or Formula III-c: wherein each of R 9 , R 10 , R 11 , and R 12 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and -N(R b )S(O) 2 R d . [00036] In some embodiments, each of R 9 , R 10 , R 11 , and R 12 is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and - N(R b )S(O) 2 R d . [00037] In some embodiments, the compound is a compound Formula III-d or Formula III-e: wherein each of R 17 and R 18 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and -N(R b )S(O) 2 R d ; and R x is H, halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , and -N(R b )S(O) 2 R d . [00038] In some embodiments, ring B is . [00039] In some embodiments, R 1 is chloro. [00040] In some embodiments, R 2 is chloro. [00041] In some embodiments, R 9 is -CH 3 . [00042] In some embodiments, R 11 is -CHF 2 . [00043] In some embodiments, R 12 is -CH 3 . [00044] In some embodiments, R 17 is -CH 3 . [00045] In some embodiments, R 18 is -CH 3 . [00046] In some embodiments, R x is -C 1 -C 6 alkyl substituted with -OH or -NH 2 . [00047] In one aspect, described herein is a compound of Formula IV: or a pharmaceutically acceptable salt thereof, wherein ring A is a sulfur-containing 5- 10 membered heteroaryl, wherein ring A is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, and - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, - N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 3 is H or -C 1 -C 6 alkyl; each of R 4 and R 5 is independently halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 6 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein -C 1 -C 6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , - N(R b )C(O)R c , and -N(R b )S(O) 2 R d , and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, - OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or - N(R b )S(O) 2 R d ; each occurrence of R a and R b is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, or two R a are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl, or two R b are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl; each occurrence of R c is H, -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of R d is independently -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo. [00048] In another aspect, described herein is a compound of Formula IV-A: or a pharmaceutically acceptable salt thereof, wherein each of R 15 , R 16 , and R 17 is independently H, halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)- N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 3 is H or -C 1 -C 6 alkyl; each of R 4 and R 5 is independently halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)- N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 6 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein -C 1 -C 6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , - N(R b )C(O)R c , and -N(R b )S(O) 2 R d , and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , and -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, - OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or - N(R b )S(O) 2 R d ; each occurrence of R a and R b is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, or two R a are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl, or two R b are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl; each occurrence of R c is H, -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of R d is independently -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo. [00049] In some embodiments, the ring B is . In some embodiments, R 15 , R 16 , and R 17 are H. In some embodiments, R 3 is H. In some embodiments, R 4 and R 5 are unsubstituted -C 1 -C 6 alkyl. In some embodiments, R 4 and R 5 are unsubstituted methyl. In some embodiments, R 6 is methyl substituted with hydroxyl. [00050] In some embodiments, the compound of Formula IV is Formula IV-B: or a pharmaceutically acceptable salt thereof, wherein each of R 15 and R 17 is independently H, halo, -OH, -CN, -N(R a )2, -C 1 -C 6 alkyl, -C 1-6 alkoxy, and -C(O)-N(R a )2, wherein each -C 1 - C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b )C(O)R c , or - N(R b )S(O) 2 R d ; R 3 is H or -C 1 -C 6 alkyl; each of R 4 and R 5 is independently halo, -OH, -CN, - N(R a ) 2 , -C 1 -C 6 alkyl, -C 1-6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 - C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 6 is halo, -OH, -CN, - N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein -C 1 -C 6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , and -N(R b )S(O) 2 R d , and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b )2, - C(O)N(R b ) 2 , and -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 - C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , or -N(R b ) 2 C(O)R c , or -N(R b )S(O) 2 R d ; each occurrence of R a and R b is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, or two R a are joined together to form a 3- 10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl, or two R b are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl; each occurrence of R c is H, -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of R d is independently -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo. [00051] In one aspect, described herein is a compound of Formula V: or a pharmaceutically acceptable salt thereof, wherein R 3 is H or -C 1 -C 6 alkyl; each of R 4 and R 5 is independently halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 6 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein -C 1 -C 6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , - N(R b )C(O)R c , and -N(R b )S(O) 2 R d , and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; ring E is a nitrogen-linked 3-10 membered heterocyclyl optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 - C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or - N(R b )S(O) 2 R d ;. ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen- containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , - C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, - OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or -N(R b )S(O) 2 R d ; each occurrence of R a and R b is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, or two R a are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl, or two R b are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl; each occurrence of R c is H, -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and - C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of R d is independently -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo. [00052] In some embodiments, ring B is . In some embodiments, ring E is N-linked piperidinyl. In some embodiments, ring E is N-linked pyrrolidinyl. In some embodiments, R 3 is H. In some embodiments, R 4 and R 5 are unsubstituted -C 1 -C 6 alkyl. In some embodiments, R 4 and R 5 are unsubstituted methyl. In some embodiments, R 6 is methyl substituted with hydroxyl. [00053] In an aspect, described herein is a compound of Formula VI: or a pharmaceutically acceptable salt thereof, wherein each of R 1 , R 2 , R 9 , R 10 , and R 11 is independently H, halo, -OH, -CN, -N(R a )2, -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)- N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy can be optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 3 is H or -C 1 -C 6 alkyl; each of R 4 and R 5 is independently halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or - C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; R 6 is halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein -C 1 -C 6 alkyl is substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , - N(R b )C(O)R c , and -N(R b )S(O) 2 R d , and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , - C(O)N(R b ) 2 , -N(R b )C(O)R c , or -N(R b )S(O) 2 R d ; ring B is a nitrogen-containing 5-10 membered heteroaryl, a nitrogen-containing 3-10 membered heterocyclyl, or phenyl, wherein ring B is optionally substituted with one or more independent occurrences of halo, -OH, -CN, -N(R a ) 2 , -C 1 -C 6 alkyl, -C 1 -C 6 alkoxy, or -C(O)-N(R a ) 2 , wherein each -C 1 -C 6 alkyl and -C 1-6 alkoxy is optionally substituted with one or more independent occurrences of halo, -OH, -C 1 -C 6 alkoxy, -N(R b ) 2 , -C(O)N(R b ) 2 , -N(R b ) 2 C(O)R c , or - N(R b )S(O) 2 R d ; X is a bond or oxygen; each occurrence of R a and R b is independently H or -C 1 -C 6 alkyl, wherein -C 1 -C 6 alkyl is optionally substituted with one or more independent occurrences of halo, or two R a are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl, or two R b are joined together to form a 3-10 membered heterocyclyl, wherein the 3-10 membered heterocyclyl is optionally substituted by one or more independent occurrences of oxo or -C 1 -C 6 alkyl; each occurrence of R c is H, -C 1 -C 6 alkyl, or -C 1 - C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo; and each occurrence of R d is independently -C 1 -C 6 alkyl, or -C 1 -C 6 alkoxy, wherein each -C 1 -C 6 alkyl and -C 1 -C 6 alkoxy is optionally substituted with one or more independent occurrences of halo. [00054] In some embodiments, ring B is . In some embodiments, R 3 is H. In some embodiments, R 4 and R 5 are unsubstituted -C 1 -C 6 alkyl. In some embodiments, R 4 and R 5 are unsubstituted methyl. In some embodiments, R 6 is methyl substituted with hydroxyl. [00055] In some embodiments, R 1 is H. [00056] In some embodiments, R 9 is H, chloro, fluoro, or -C 1 -C 6 alkyl, wherein the -C 1 - C 6 alkyl can be optionally substituted with one or more independent occurrences of halo. In some embodiments, R 9 is -CF 3 . [00057] In some embodiments, R 10 is H, -C 1 -C 6 alkyl, fluoro, or chloro. [00058] In some embodiments, R 2 is H, fluoro, or -C 1 -C 6 alkyl. [00059] In some embodiments, R 11 is H, chloro, fluoro, -C 1 -C 6 alkoxy, or -C 1 -C 6 alkyl, wherein the , -C 1 -C 6 alkoxy and -C 1 -C 6 alkyl can be optionally substituted with one or more independent occurrences of halo. In some embodiments, R 11 is -OCH 3 , -OCH 2 CH 3 , or - OCF 3 , . In some embodiments, R 11 is -CF 3 . [00060] In some embodiments, the compound is a compound identified in Table 1 below or a pharmaceutically acceptable salt thereof. Table 1. Exemplary compounds.
Alternative Embodiments [00061] In an alternative embodiment, compounds of Formula I, II, III, IV, V, VI, or subgenera thereof, may also comprise one or more isotopic substitutions. For example, hydrogen may be 2 H (D or deuterium) or 3 H (T or tritium); carbon may be, for example, 13 C or 14 C; oxygen may be, for example, 18 O; nitrogen may be, for example, 15 N, and the like. In other embodiments, a particular isotope (e.g., 3 H, 13 C, 14 C, 18 O, or 15 N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. Chemical Definitions [00062] Definitions of specific functional groups and chemical terms are described in more detail below. The chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 th Ed., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March’s Advanced Organic Chemistry, 5 th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3 rd Edition, Cambridge University Press, Cambridge, 1987. [00063] The articles “a” and “an” may be used herein to refer to one or to more than one (i.e. at least one) of the grammatical objects of the article. By way of example “an analogue” means one analogue or more than one analogue. [00064] When a range of values is listed, it is intended to encompass each value and sub– range within the range. For example “C 1–6 alkyl” is intended to encompass, C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1–6 , C 1–5 , C 1–4 , C 1–3 , C 1–2 , C 2–6 , C 2–5 , C 2–4 , C 2–3 , C 3–6 , C 3–5 , C 3–4 , C 4–6 , C 4–5 , and C 5–6 alkyl. [00065] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention. [00066] “Alkyl” refers to a radical of a straight–chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1–20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1–12 alkyl”). In some embodiments, an alkyl group has 1 to 10 carbon atoms (“C 1–10 alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C 1–9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1–8 alkyl”). In some embodiments, an alkyl group has 1 to 7 carbon atoms (“C 1–7 alkyl”). In some embodiments, an alkyl group has 1 to 6 carbon atoms (“C 1–6 alkyl”, also referred to herein as “lower alkyl”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1– 5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1–4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1–3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C 1–2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“C 1 alkyl”). In some embodiments, an alkyl group has 2 to 6 carbon atoms (“C 2–6 alkyl”). Examples of C 1–6 alkyl groups include methyl (C 1 ), ethyl (C 2 ), n–propyl (C 3 ), isopropyl (C 3 ), n–butyl (C 4 ), tert–butyl (C 4 ), sec–butyl (C 4 ), iso–butyl (C 4 ), n– pentyl (C 5 ), 3–pentanyl (C 5 ), amyl (C 5 ), neopentyl (C 5 ), 3–methyl–2–butanyl (C 5 ), tertiary amyl (C 5 ), and n–hexyl (C 6 ). Additional examples of alkyl groups include n–heptyl (C 7 ), n– octyl (C 8 ) and the like. Unless otherwise specified, each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkyl group is unsubstituted C 1–10 alkyl (e.g., –CH 3 ). In certain embodiments, the alkyl group is substituted C 1–10 alkyl. Common alkyl abbreviations include Me (-CH 3 ), Et (-CH 2 CH 3 ), iPr (- CH(CH 3 ) 2 ), nPr (-CH 2 CH 2 CH 3 ), n-Bu (-CH 2 CH 2 CH 2 CH 3 ), or i-Bu (-CH 2 CH(CH 3 ) 2 ). [00067] “Alkylene” refers to an alkyl group wherein two hydrogens are removed to provide a divalent radical, and which may be substituted or unsubstituted. Unsubstituted alkylene groups include, but are not limited to, methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), butylene (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 - ), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -), and the like. Exemplary substituted alkylene groups, e.g., substituted with one or more alkyl (methyl) groups, include but are not limited to, substituted methylene (-CH(CH 3 )-, (-C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -,- CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -,-CH 2 C(CH 3 ) 2 -), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, - CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, - CH 2 CH 2 C(CH 3 ) 2 -), and the like. When a range or number of carbons is provided for a particular alkylene group, it is understood that the range or number refers to the range or number of carbons in the linear carbon divalent chain. Alkylene groups may be substituted or unsubstituted with one or more substituents as described herein. [00068] “Alkenyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds), and optionally one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds) (“C 2–20 alkenyl”). In certain embodiments, alkenyl does not contain any triple bonds. In some embodiments, an alkenyl group has 2 to 10 carbon atoms (“C 2–10 alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms (“C 2–9 alkenyl”). In some embodiments, an alkenyl group has 2 to 8 carbon atoms (“C 2–8 alkenyl”). In some embodiments, an alkenyl group has 2 to 7 carbon atoms (“C 2–7 alkenyl”). In some embodiments, an alkenyl group has 2 to 6 carbon atoms (“C 2–6 alkenyl”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C 2–5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C 2–4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C 2–3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C 2 alkenyl”). The one or more carbon–carbon double bonds can be internal (such as in 2–butenyl) or terminal (such as in 1– butenyl). Examples of C 2–4 alkenyl groups include ethenyl (C 2 ), 1–propenyl (C 3 ), 2–propenyl (C 3 ), 1–butenyl (C 4 ), 2–butenyl (C 4 ), butadienyl (C 4 ), and the like. Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C 7 ), octenyl (C 8 ), octatrienyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkenyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkenyl group is unsubstituted C 2–10 alkenyl. In certain embodiments, the alkenyl group is substituted C 2–10 alkenyl. [00069] “Alkynyl” refers to a radical of a straight–chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon–carbon triple bonds (e.g., 1, 2, 3, or 4 carbon–carbon triple bonds), and optionally one or more carbon–carbon double bonds (e.g., 1, 2, 3, or 4 carbon–carbon double bonds) (“C 2–20 alkynyl”). In certain embodiments, alkynyl does not contain any double bonds. In some embodiments, an alkynyl group has 2 to 10 carbon atoms (“C 2–10 alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms (“C 2–9 alkynyl”). In some embodiments, an alkynyl group has 2 to 8 carbon atoms (“C 2–8 alkynyl”). In some embodiments, an alkynyl group has 2 to 7 carbon atoms (“C 2–7 alkynyl”). In some embodiments, an alkynyl group has 2 to 6 carbon atoms (“C 2–6 alkynyl”). In some embodiments, an alkynyl group has 2 to 5 carbon atoms (“C 2–5 alkynyl”). In some embodiments, an alkynyl group has 2 to 4 carbon atoms (“C 2–4 alkynyl”). In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C 2–3 alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C 2 alkynyl”). The one or more carbon– carbon triple bonds can be internal (such as in 2–butynyl) or terminal (such as in 1–butynyl). Examples of C 2–4 alkynyl groups include, without limitation, ethynyl (C 2 ), 1–propynyl (C 3 ), 2–propynyl (C 3 ), 1–butynyl (C 4 ), 2–butynyl (C 4 ), and the like. Examples of C 2–6 alkenyl groups include the aforementioned C 2–4 alkynyl groups as well as pentynyl (C 5 ), hexynyl (C 6 ), and the like. Additional examples of alkynyl include heptynyl (C 7 ), octynyl (C 8 ), and the like. Unless otherwise specified, each instance of an alkynyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkynyl”) or substituted (a “substituted alkynyl”) with one or more substituents; e.g., for instance from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. In certain embodiments, the alkynyl group is unsubstituted C 2–10 alkynyl. In certain embodiments, the alkynyl group is substituted C 2–10 alkynyl. [00070] “Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 π electrons shared in a cyclic array) having 6–14 ring carbon atoms and zero heteroatoms provided in the aromatic ring system (“C 6–14 aryl”). In some embodiments, an aryl group has six ring carbon atoms (“C 6 aryl”; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms (“C 10 aryl”; e.g., naphthyl such as 1–naphthyl and 2–naphthyl). In some embodiments, an aryl group has fourteen ring carbon atoms (“C 14 aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein the aryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the radical or point of attachment is on the aryl ring, and in such instances, the number of carbon atoms continue to designate the number of carbon atoms in the aryl ring system. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, and trinaphthalene. Particularly aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl. Unless otherwise specified, each instance of an aryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted aryl”) or substituted (a “substituted aryl”) with one or more substituents. In certain embodiments, the aryl group is unsubstituted C 6–14 aryl. In certain embodiments, the aryl group is substituted C6–14 aryl. [00071] In certain embodiments, an aryl group substituted with one or more of groups selected from halo, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, cyano, hydroxy, C 1 -C 8 alkoxy, and amino. [00072] An example of representative substituted aryls is wherein one of R 56 and R 57 may be hydrogen and at least one of R 56 and R 57 is each independently selected from C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, 4-10 membered heterocyclyl, alkanoyl, C 1 -C 8 alkoxy, heteroaryloxy, alkylamino, arylamino, heteroarylamino, NR 58 COR 59 , NR 58 SOR 59 NR 58 SO 2 R 59 , COOalkyl, COOaryl, CONR 58 R 59 , CONR 58 OR 59 , NR 58 R 59 , SO 2 NR 58 R 59 , S-alkyl, SOalkyl, SO 2 alkyl, Saryl, SOaryl, SO 2 aryl; or R 56 and R 57 may be joined to form a cyclic ring (saturated or unsaturated) from 5 to 8 atoms, optionally containing one or more heteroatoms selected from the group N, O, or S. R 60 and R 61 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 4 haloalkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, substituted C 6 -C 10 aryl, 5-10 membered heteroaryl, or substituted 5- 10 membered heteroaryl . [00073] “Heteroaryl” refers to a radical of a 5–10 membered monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electrons shared in a cyclic array) having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur (“5–10 membered heteroaryl”). In heteroaryl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. Heteroaryl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heteroaryl” includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more carbocyclyl or heterocyclyl groups wherein the point of attachment is on the heteroaryl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heteroaryl ring system. “Heteroaryl” also includes ring systems wherein the heteroaryl ring, as defined above, is fused with one or more aryl groups wherein the point of attachment is either on the aryl or heteroaryl ring, and in such instances, the number of ring members designates the number of ring members in the fused (aryl/heteroaryl) ring system. Bicyclic heteroaryl groups wherein one ring does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of attachment can be on either ring, i.e., either the ring bearing a heteroatom (e.g., 2–indolyl) or the ring that does not contain a heteroatom (e.g., 5–indolyl). [00074] In some embodiments, a heteroaryl group is a 5–10 membered aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–10 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5–8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In some embodiments, a heteroaryl group is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Unless otherwise specified, each instance of a heteroaryl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heteroaryl”) or substituted (a “substituted heteroaryl”) with one or more substituents. In certain embodiments, the heteroaryl group is unsubstituted 5-14 membered heteroaryl. In certain embodiments, the heteroaryl group is substituted 5-14 membered heteroaryl.
[00075] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotri azolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadi azolyl, benzthiazolyl, benzisothiazolyl, benzthiadi azolyl, indolizinyl, and purinyl. Exemplary 6,6- bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. [00076] Examples of representative heteroaryls include the following: wherein each Z is selected from carbonyl, N, NR 65 , O, and S; and R 65 is independently hydrogen, C 1 -C 8 alkyl, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, C 6 -C 10 aryl, and 5-10 membered heteroaryl. [00077] “Carbocyclyl” or “carbocyclic” refers to a radical of a non–aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C 3–10 carbocyclyl”) and zero heteroatoms in the non–aromatic ring system. In some embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms (“C 3–8 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms (“C 3–6 carbocyclyl”). In some embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms (“C 5–10 carbocyclyl”). Exemplary C 3–6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like. Exemplary C 3–8 carbocyclyl groups include, without limitation, the aforementioned C 3–6 carbocyclyl groups as well as cycloheptyl (C 7 ), cycloheptenyl (C 7 ), cycloheptadienyl (C 7 ), cycloheptatrienyl (C 7 ), cyclooctyl (C 8 ), cyclooctenyl (C 8 ), bicyclo[2.2.1]heptanyl (C 7 ), bicyclo[2.2.2]octanyl (C8), and the like. Exemplary C 3–10 carbocyclyl groups include, without limitation, the aforementioned C 3–8 carbocyclyl groups as well as cyclononyl (C 9 ), cyclononenyl (C 9 ), cyclodecyl (C 10 ), cyclodecenyl (C 10 ), octahydro–1H–indenyl (C 9 ), decahydronaphthalenyl (C 10 ), spiro[4.5]decanyl (C 10 ), and the like. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated. “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system. Unless otherwise specified, each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents. In certain embodiments, the carbocyclyl group is unsubstituted C 3–10 carbocyclyl. In certain embodiments, the carbocyclyl group is a substituted C 3–10 carbocyclyl. [00078] In some embodiments, “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C 3–10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C 3–8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C 3–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C 5–6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C 5–10 cycloalkyl”). Examples of C 5–6 cycloalkyl groups include cyclopentyl (C 5 ) and cyclohexyl (C 5 ). Examples of C 3–6 cycloalkyl groups include the aforementioned C 5–6 cycloalkyl groups as well as cyclopropyl (C 3 ) and cyclobutyl (C 4 ). Examples of C 3–8 cycloalkyl groups include the aforementioned C 3–6 cycloalkyl groups as well as cycloheptyl (C 7 ) and cyclooctyl (C 8 ). Unless otherwise specified, each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents. In certain embodiments, the cycloalkyl group is unsubstituted C 3–10 cycloalkyl. In certain embodiments, the cycloalkyl group is substituted C 3–10 cycloalkyl. [00079] “Heterocyclyl” or “heterocyclic” refers to a radical of a 3– to 10–membered non– aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3–10 membered heterocyclyl”). In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”), and can be saturated or can be partially unsaturated. Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings. “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system. Unless otherwise specified, each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents. In certain embodiments, the heterocyclyl group is unsubstituted 3–10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3–10 membered heterocyclyl. [00080] In some embodiments, a heterocyclyl group is a 5–10 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5–10 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–8 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–8 membered heterocyclyl”). In some embodiments, a heterocyclyl group is a 5–6 membered non–aromatic ring system having ring carbon atoms and 1–4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5–6 membered heterocyclyl”). In some embodiments, the 5–6 membered heterocyclyl has 1–3 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has 1–2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In some embodiments, the 5–6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur. [00081] Exemplary 3–membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4–membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5–membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl–2,5–dione. Exemplary 5– membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5–membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6–membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6–membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl. Exemplary 6– membered heterocyclyl groups containing two heteroatoms include, without limitation, triazinanyl. Exemplary 7–membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8–membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered heterocyclyl groups fused to a C 6 aryl ring (also referred to herein as a 5,6-bicyclic heterocyclic ring) include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groups fused to an aryl ring (also referred to herein as a 6,6-bicyclic heterocyclic ring) include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. [00082] “Nitrogen-containing heterocyclyl” group means a 4- to 7- membered non- aromatic cyclic group containing at least one nitrogen atom, for example, but without limitation, morpholine, piperidine (e.g.2-piperidinyl, 3-piperidinyl and 4-piperidinyl), pyrrolidine (e.g.2-pyrrolidinyl and 3-pyrrolidinyl), azetidine, pyrrolidone, imidazoline, imidazolidinone, 2-pyrazoline, pyrazolidine, piperazine, and N-alkyl piperazines such as N- methyl piperazine. Particular examples include azetidine, piperidone and piperazone. [00083] “Hetero” when used to describe a compound or a group present on a compound means that one or more carbon atoms in the compound or group have been replaced by a nitrogen, oxygen, or sulfur heteroatom. Hetero may be applied to any of the hydrocarbyl groups described above such as alkyl, e.g., heteroalkyl, cycloalkyl, e.g., heterocyclyl, aryl, e.g,. heteroaryl, cycloalkenyl, e.g,. cycloheteroalkenyl, and the like having from 1 to 5, and particularly from 1 to 3 heteroatoms. [00084] “Alkoxy” refers to the group –OR 29 where R 29 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Particular alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n- hexoxy, and 1,2-dimethylbutoxy. Particular alkoxy groups are lower alkoxy, i.e. with between 1 and 6 carbon atoms. Further particular alkoxy groups have between 1 and 4 carbon atoms. [00085] In certain embodiments, R 29 is a group that has 1 or more substituents, for instance from 1 to 5 substituents, and particularly from 1 to 3 substituents, in particular 1 substituent, selected from the group consisting of amino, substituted amino, C 6 -C 10 aryl, aryloxy, carboxyl, cyano, C 3 -C 10 cycloalkyl, 4-10 membered heterocyclyl, halogen, 5-10 membered heteroaryl, hydroxyl, nitro, thioalkoxy, thioaryloxy, thiol, alkyl-S(O)-, aryl–S(O)-, alkyl–S(O) 2 - and aryl-S(O) 2 -. Exemplary ‘substituted alkoxy’ groups include, but are not limited to, –O-(CH 2 ) t (C 6 -C 10 aryl), –O-(CH 2 ) t (5-10 membered heteroaryl), –O-(CH 2 ) t (C 3 -C 10 cycloalkyl), and –O-(CH 2 ) t (4-10 membered heterocyclyl), wherein t is an integer from 0 to 4 and any aryl, heteroaryl, cycloalkyl or heterocyclyl groups present, may themselves be substituted by unsubstituted C 1 -C 4 alkyl, halo, unsubstituted C 1 -C 4 alkoxy, unsubstituted C 1 - C 4 haloalkyl, unsubstituted C 1 -C 4 hydroxyalkyl, or unsubstituted C 1 -C 4 haloalkoxy or hydroxy. Particular exemplary ‘substituted alkoxy’ groups are -OCF 3 , -OCH 2 CF 3 , -OCH 2 Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 OH, and -OCH 2 CH 2 NMe 2 . [00086] “Oxo group” refers to –C(=O)–. [00087] “Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), and iodo (I). In certain embodiments, the halo group is either fluoro or chloro. [00088] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl groups, as defined herein, are optionally substituted (e.g., “substituted” or “unsubstituted” alkyl, “substituted” or “unsubstituted” alkenyl, “substituted” or “unsubstituted” alkynyl, “substituted” or “unsubstituted” carbocyclyl, “substituted” or “unsubstituted” heterocyclyl, “substituted” or “unsubstituted” aryl or “substituted” or “unsubstituted” heteroaryl group). In general, the term “substituted”, whether preceded by the term “optionally” or not, means that at least one hydrogen present on a group (e.g., a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction. Unless otherwise indicated, a “substituted” group has a substituent at one or more substitutable positions of the group, and when more than one position in any given structure is substituted, the substituent is either the same or different at each position. The term “substituted” is contemplated to include substitution with all permissible substituents of organic compounds, any of the substituents described herein that results in the formation of a stable compound. The present invention contemplates any and all such combinations in order to arrive at a stable compound. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any suitable substituent as described herein which satisfy the valencies of the heteroatoms and results in the formation of a stable moiety. [00089] Exemplary carbon atom substituents include, but are not limited to, halogen, – CN, –NO 2 , –N 3 , –SO 2 H, –SO 3 H, –OH, –OR aa , –ON(R bb ) 2 , –N(R bb ) 2 , –N(R bb ) 3 + X – , – N(OR cc )R bb , –SH, –SR aa , –SSR cc , –C(=O)R aa , –CO 2 H, –CHO, –C(OR cc ) 2 , –CO 2 R aa , – OC(=O)R aa , –OCO 2 R aa , –C(=O)N(R bb ) 2 , –OC(=O)N(R bb ) 2 , –NR bb C(=O)R aa , –NR bb CO 2 R aa , – NR bb C(=O)N(R bb ) 2 , –C(=NR bb )R aa , –C(=NR bb )OR aa , –OC(=NR bb )R aa , –OC(=NR bb )OR aa , – C(=NR bb )N(R bb ) 2 , –OC(=NR bb )N(R bb ) 2 , –NR bb C(=NR bb )N(R bb ) 2 , –C(=O)NR bb SO 2 R aa , – NR bb SO 2 R aa , –SO 2 N(R bb ) 2 , –SO 2 R aa , –SO 2 OR aa , –OSO 2 R aa , –S(=O)R aa , –OS(=O)R aa , – Si(R aa ) 3 , –OSi(R aa ) 3 –C(=S)N(R bb ) 2 , –C(=O)SR aa , –C(=S)SR aa , –SC(=S)SR aa , –SC(=O)SR aa , –OC(=O)SR aa , –SC(=O)OR aa , –SC(=O)R aa , –P(=O) 2 R aa , –OP(=O) 2 R aa , –P(=O)(R aa ) 2 , – OP(=O)(R aa ) 2 , –OP(=O)(OR cc ) 2 , –P(=O) 2 N(R bb ) 2 , –OP(=O) 2 N(R bb ) 2 , –P(=O)(NR bb ) 2 , – OP(=O)(NR bb ) 2 , –NR bb P(=O)(OR cc ) 2 , –NR bb P(=O)(NR bb ) 2 , –P(R cc ) 2 , –P(R cc ) 3 , –OP(R cc ) 2 , – OP(R cc ) 3 , –B(R aa ) 2 , –B(OR cc ) 2 , –BR aa (OR cc ), C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; or two geminal hydrogens on a carbon atom are replaced with the group =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , =NNR bb S(=O) 2 R aa , =NR bb , or =NOR cc ; each instance of R aa is, independently, selected from C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, or two R aa groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R bb is, independently, selected from hydrogen, –OH, –OR aa , –N(R cc ) 2 , –CN, – C(=O)R aa , –C(=O)N(R cc ) 2 , –CO 2 R aa , –SO 2 R aa , –C(=NR cc )OR aa , –C(=NR cc )N(R cc ) 2 , – SO 2 N(R cc ) 2 , –SO 2 R cc , –SO 2 OR cc , –SOR aa , –C(=S)N(R cc ) 2 , –C(=O)SR cc , –C(=S)SR cc , – P(=O) 2 R aa , –P(=O)(R aa ) 2 , –P(=O) 2 N(R cc ) 2 , –P(=O)(NR cc ) 2 , C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, or two R bb groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R cc is, independently, selected from hydrogen, C 1–10 alkyl, C 1–10 haloalkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14 membered heterocyclyl, C 6–14 aryl, and 5–14 membered heteroaryl, or two R cc groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R dd is, independently, selected from halogen, –CN, –NO 2 , – N 3 , –SO 2 H, –SO 3 H, –OH, –OR ee , –ON(R ff ) 2 , –N(R ff ) 2 , –N(R ff ) 3 + X – , –N(OR ee )R ff , –SH, – SR ee , –SSR ee , –C(=O)R ee , –CO 2 H, –CO 2 R ee , –OC(=O)R ee , –OCO 2 R ee , –C(=O)N(R ff ) 2 , – OC(=O)N(R ff ) 2 , –NR ff C(=O)R ee , –NR ff CO 2 R ee , –NR ff C(=O)N(R ff ) 2 , –C(=NR ff )OR ee , – OC(=NR ff )R ee , –OC(=NR ff )OR ee , –C(=NR ff )N(R ff ) 2 , –OC(=NR ff )N(R ff ) 2 , – NR ff C(=NR ff )N(R ff ) 2 ,–NR ff SO 2 R ee , –SO 2 N(R ff ) 2 , –SO 2 R ee , –SO 2 OR ee , –OSO 2 R ee , –S(=O)R ee , –Si(R ee ) 3 , –OSi(R ee ) 3 , –C(=S)N(R ff ) 2 , –C(=O)SR ee , –C(=S)SR ee , –SC(=S)SR ee , –P(=O) 2 R ee , – P(=O)(R ee ) 2 , –OP(=O)(R ee ) 2 , –OP(=O)(OR ee ) 2 , C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, 3–10 membered heterocyclyl, C 6–10 aryl, 5–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups, or two geminal R dd substituents can be joined to form =O or =S; each instance of R ee is, independently, selected from C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, C 6–10 aryl, 3–10 membered heterocyclyl, and 3–10 membered heteroaryl, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; each instance of R ff is, independently, selected from hydrogen, C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, 3–10 membered heterocyclyl, C 6–10 aryl and 5–10 membered heteroaryl, or two R ff groups are joined to form a 3–14 membered heterocyclyl or 5–14 membered heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R gg groups; and each instance of R gg is, independently, halogen, –CN, –NO 2 , –N 3 , –SO 2 H, –SO 3 H, –OH, –OC 1–6 alkyl, –ON(C 1–6 alkyl) 2 , –N(C 1–6 alkyl) 2 , –N(C 1–6 alkyl) 3 + X – , –NH(C 1–6 alkyl) 2 + X – , –NH 2 (C 1–6 alkyl) + X – , –NH 3 + X – , –N(OC 1–6 alkyl)(C 1–6 alkyl), – N(OH)(C 1–6 alkyl), –NH(OH), –SH, –SC 1–6 alkyl, –SS(C 1–6 alkyl), –C(=O)(C 1–6 alkyl), – CO 2 H, –CO 2 (C 1–6 alkyl), –OC(=O)(C 1–6 alkyl), –OCO 2 (C 1–6 alkyl), –C(=O)NH 2 , – C(=O)N(C 1–6 alkyl) 2 , –OC(=O)NH(C 1–6 alkyl), –NHC(=O)( C 1–6 alkyl), –N(C 1–6 alkyl)C(=O)( C 1–6 alkyl), –NHCO 2 (C 1–6 alkyl), –NHC(=O)N(C 1–6 alkyl) 2 , –NHC(=O)NH(C 1– 6 alkyl), –NHC(=O)NH 2 , –C(=NH)O(C 1–6 alkyl),–OC(=NH)(C 1–6 alkyl), –OC(=NH)OC 1–6 alkyl, –C(=NH)N(C 1–6 alkyl) 2 , –C(=NH)NH(C 1–6 alkyl), –C(=NH)NH 2 , –OC(=NH)N(C 1–6 alkyl) 2 , –OC(NH)NH(C 1–6 alkyl), –OC(NH)NH 2 , –NHC(NH)N(C 1–6 alkyl) 2 , – NHC(=NH)NH 2 , –NHSO 2 (C 1–6 alkyl), –SO 2 N(C 1–6 alkyl) 2 , –SO 2 NH(C 1–6 alkyl), –SO 2 NH 2 ,– SO 2 C 1–6 alkyl, –SO 2 OC 1–6 alkyl, –OSO 2 C 1–6 alkyl, –SOC 1–6 alkyl, –Si(C 1–6 alkyl) 3 , –OSi(C 1–6 alkyl) 3 –C(=S)N(C 1–6 alkyl) 2 , C(=S)NH(C 1–6 alkyl), C(=S)NH 2 , –C(=O)S(C 1–6 alkyl), – C(=S)SC 1–6 alkyl, –SC(=S)SC 1–6 alkyl, –P(=O) 2 (C 1–6 alkyl), –P(=O)(C 1–6 alkyl) 2 , – OP(=O)(C 1–6 alkyl) 2 , –OP(=O)(OC 1–6 alkyl) 2 , C 1–6 alkyl, C 1–6 haloalkyl, C 2–6 alkenyl, C 2–6 alkynyl, C 3–10 carbocyclyl, C 6–10 aryl, 3–10 membered heterocyclyl, 5–10 membered heteroaryl; or two geminal R gg substituents can be joined to form =O or =S; wherein X – is a counterion. [00090] In certain embodiments, the substituent present on an oxygen atom is an oxygen protecting group (also referred to as a hydroxyl protecting group). Oxygen protecting groups include, but are not limited to, –R aa , –N(R bb ) 2 , –C(=O)SR aa , –C(=O)R aa , –CO 2 R aa , – C(=O)N(R bb ) 2 , –C(=NR bb )R aa , –C(=NR bb )OR aa , –C(=NR bb )N(R bb ) 2 , –S(=O)R aa , –SO 2 R aa , – Si(R aa ) 3, –P(R cc ) 2 , –P(R cc ) 3 , –P(=O) 2 R aa , –P(=O)(R aa ) 2 , –P(=O)(OR cc ) 2 , –P(=O) 2 N(R bb ) 2 , and – P(=O)(NR bb ) 2 , wherein R aa , R bb , and R cc are as defined herein. Oxygen protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [00091] Exemplary oxygen protecting groups include, but are not limited to, methyl, methoxylmethyl (MOM), 2–methoxyethoxymethyl (MEM), benzyl (Bn), triisopropylsilyl (TIPS), t–butyldimethylsilyl (TBDMS), t–butylmethoxyphenylsilyl (TBMPS), methanesulfonate (mesylate), and tosylate (Ts). [00092] In certain embodiments, the substituent present on an sulfur atom is an sulfur protecting group (also referred to as a thiol protecting group). Sulfur protecting groups include, but are not limited to, –R aa , –N(R bb ) 2 , –C(=O)SR aa , –C(=O)R aa , –CO 2 R aa , – C(=O)N(R bb ) 2 , –C(=NR bb )R aa , –C(=NR bb )OR aa , –C(=NR bb )N(R bb ) 2 , –S(=O)R aa , –SO 2 R aa , – Si(R aa ) 3, –P(R cc ) 2 , –P(R cc ) 3 , –P(=O) 2 R aa , –P(=O)(R aa ) 2 , –P(=O)(OR cc ) 2 , –P(=O) 2 N(R bb ) 2 , and – P(=O)(NR bb ) 2 , wherein R aa , R bb , and R cc are as defined herein. Sulfur protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [00093] In certain embodiments, the substituent present on a nitrogen atom is an amino protecting group (also referred to herein as a nitrogen protecting group). Amino protecting groups include, but are not limited to, –OH, –OR aa , –N(R cc ) 2 , –C(=O)R aa , –C(=O)OR aa , – C(=O)N(R cc ) 2 , –S(=O) 2 R aa , –C(=NR cc )R aa , –C(=NR cc )OR aa , –C(=NR cc )N(R cc ) 2 , –SO 2 N(R cc ) 2 , –SO 2 R cc , –SO 2 OR cc , –SOR aa , –C(=S)N(R cc ) 2 , –C(=O)SR cc , –C(=S)SR cc , C 1–10 alkyl, C 2–10 alkenyl, C 2–10 alkynyl, C 3–10 carbocyclyl, 3–14–membered heterocyclyl, C 6–14 aryl, and 5–14– membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups, and wherein R aa , R bb , R cc and R dd are as defined herein. Amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3 rd edition, John Wiley & Sons, 1999, incorporated herein by reference. [00094] Exemplary amino protecting groups include, but are not limited to amide groups (e.g., –C(=O)R aa ), which include, but are not limited to, formamide and acetamide; carbamate groups (e.g., –C(=O)OR aa ), which include, but are not limited to, 9– fluorenylmethyl carbamate (Fmoc), t–butyl carbamate (BOC), and benzyl carbamate (Cbz); sulfonamide groups (e.g., –S(=O) 2 R aa ), which include, but are not limited to, p– toluenesulfonamide (Ts), methanesulfonamide (Ms), and N–[2– (trimethylsilyl)ethoxy]methylamine (SEM). Pharmaceutical Compositions [00095] In one aspect, provided herein is a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I) or Formula (II)) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. In certain embodiments, the compound of the present invention is provided in an effective amount in the pharmaceutical composition. In certain embodiments, the compound of the present invention is provided in a therapeutically effective amount. In certain embodiments, the compound of the present invention is provided in a prophylactically effective amount. [00096] In certain embodiments, the pharmaceutical composition comprises an effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a therapeutically effective amount of the active ingredient. In certain embodiments, the pharmaceutical composition comprises a prophylactically effective amount of the active ingredient. [00097] The pharmaceutical compositions provided herein can be administered by a variety of routes including, but not limited to, oral (enteral) administration, parenteral (by injection) administration, rectal administration, transdermal administration, intradermal administration, intrathecal administration, subcutaneous (SC) administration, intravenous (IV) administration, intramuscular (IM) administration, and intranasal administration. [00098] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient’s symptoms, and the like. [00099] When used to prevent the onset of a neurological-disorder, the compounds provided herein will be administered to a subject at risk for developing the condition, typically on the advice and under the supervision of a physician, at the dosage levels described above. Subjects at risk for developing a particular condition generally include those that have a family history of the condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the condition. [000100] The pharmaceutical compositions provided herein can also be administered chronically (“chronic administration”). Chronic administration refers to administration of a compound or pharmaceutical composition thereof over an extended period of time, e.g., for example, over 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc, or may be continued indefinitely, for example, for the rest of the subject’s life. In certain embodiments, the chronic administration is intended to provide a constant level of the compound in the blood, e.g., within the therapeutic window over the extended period of time. [000101] The pharmaceutical compositions of the present invention may be further delivered using a variety of dosing methods. For example, in certain embodiments, the pharmaceutical composition may be given as a bolus, e.g., in order to raise the concentration of the compound in the blood to an effective level. The placement of the bolus dose depends on the systemic levels of the active ingredient desired throughout the body, e.g., an intramuscular or subcutaneous bolus dose allows a slow release of the active ingredient, while a bolus delivered directly to the veins (e.g., through an IV drip) allows a much faster delivery which quickly raises the concentration of the active ingredient in the blood to an effective level. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, e.g., by IV drip, to provide maintenance of a steady-state concentration of the active ingredient in the subject’s body. Furthermore, in still yet other embodiments, the pharmaceutical composition may be administered as first as a bolus dose, followed by continuous infusion. [000102] The compositions for oral administration can take the form of bulk liquid solutions or suspensions, or bulk powders. More commonly, however, the compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the compound is usually a minor component (from about 0.1 to about 50% by weight or preferably from about 1 to about 40% by weight) with the remainder being various vehicles or excipients and processing aids helpful for forming the desired dosing form. [000103] With oral dosing, one to five and especially two to four and typically three oral doses per day are representative regimens. Using these dosing patterns, each dose provides from about 0.01 to about 20 mg/kg of the compound provided herein, with preferred doses each providing from about 0.1 to about 10 mg/kg, and especially about 1 to about 5 mg/kg. [000104] Transdermal doses are generally selected to provide similar or lower blood levels than are achieved using injection doses, generally in an amount ranging from about 0.01 to about 20% by weight, preferably from about 0.1 to about 20% by weight, preferably from about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight. [000105] Injection dose levels range from about 0.1 mg/kg/hour to at least 20 mg/kg/hour, all for from about 1 to about 120 hours and especially 24 to 96 hours. A preloading bolus of from about 0.1 mg/kg to about 10 mg/kg or more may also be administered to achieve adequate steady state levels. The maximum total dose is not expected to exceed about 5 g/day for a 40 to 80 kg human patient.
[000106] Liquid forms suitable for oral administration may include a suitable aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors and the like. Solid forms may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
[000107] Injectable compositions are typically based upon injectable sterile saline or phosphate-buffered saline or other injectable excipients known in the art. As before, the active compound in such compositions is typically a minor component, often being from about 0.05 to 10% by weight with the remainder being the injectable excipient and the like.
[000108] Transdermal compositions are typically formulated as a topical ointment or cream containing the active ingredient(s). When formulated as an ointment, the active ingredients will typically be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations are well-known in the art and generally include additional ingredients to enhance the dermal penetration of stability of the active ingredients or formulation. All such known transdermal formulations and ingredients are included within the scope provided herein.
[000109] The compounds provided herein can also be administered by a transdermal device. Accordingly, transdermal administration can be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.
[000110] The above-described components for orally administrable, injectable or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington ’s Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference. [000111] The compounds of the present invention can also be administered in sustained release forms or from sustained release drug delivery systems. A description of representative sustained release materials can be found in Remington’s Pharmaceutical Sciences. [000112] The present invention also relates to the pharmaceutically acceptable acid addition salt of a compound of the present invention. The acid which may be used to prepare the pharmaceutically acceptable salt is that which forms a non-toxic acid addition salt, i.e., a salt containing pharmacologically acceptable anions such as the hydrochloride, hydroiodide, hydrobromide, nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate, succinate, maleate, fumarate, benzoate, para-toluenesulfonate, and the like. [000113] In another aspect, the invention provides a pharmaceutical composition comprising a compound of the present invention and a pharmaceutically acceptable excipient, e.g., a composition suitable for injection, such as for intravenous (IV) administration. [000114] Pharmaceutically acceptable excipients include any and all diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, preservatives, lubricants and the like, as suited to the particular dosage form desired, e.g., injection. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21 st Edition (Lippincott Williams & Wilkins, 2005). [000115] For example, injectable preparations, such as sterile injectable aqueous suspensions, can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. Exemplary excipients that can be employed include, but are not limited to, water, sterile saline or phosphate–buffered saline, or Ringer's solution. [000116] The injectable composition can be sterilized, for example, by filtration through a bacterial–retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. [000117] Generally, the compounds provided herein are administered in an effective amount. The amount of the compound actually administered will typically be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, response of the individual patient, the severity of the patient’s symptoms, and the like. [000118] The compositions are presented in unit dosage forms to facilitate accurate dosing. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Typical unit dosage forms include pre–filled, pre– measured ampules or syringes of the liquid compositions. In such compositions, the compound is usually a minor component (from about 0.1% to about 50% by weight or preferably from about 1% to about 40% by weight) with the remainder being various vehicles or carriers and processing aids helpful for forming the desired dosing form. [000119] The compounds provided herein can be administered as the sole active agent, or they can be administered in combination with other active agents. In one aspect, the present invention provides a combination of a compound of the present invention and another pharmacologically active agent. Administration in combination can proceed by any technique apparent to those of skill in the art including, for example, separate, sequential, concurrent, and alternating administration. [000120] Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005. [000121] In one aspect, provided is a kit comprising a composition (e.g., a solid composition) comprising a compound of Formula I, II, III, IV, V, VI, or subgenera thereof. Pharmaceutical Composition Definitions [000122] “Pharmaceutically acceptable” means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, and more particularly, in humans. [000123] “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. In particular, such salts are non–toxic may be inorganic or organic acid addition salts and base addition salts. Specifically, such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, formic acid, tartaric acid, citric acid, benzoic acid, 3–(4–hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2–ethane–disulfonic acid, 2– hydroxyethanesulfonic acid, benzenesulfonic acid, 4–chlorobenzenesulfonic acid, 2– naphthalenesulfonic acid, 4–toluenesulfonic acid, camphorsulfonic acid, 4– methylbicyclo[2.2.2]–oct–2–ene–1–carboxylic acid, glucoheptonic acid, 3–phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N– methylglucamine and the like. Salts further include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the compound contains a basic functionality, salts of non-toxic organic or inorganic acids, such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, formate, oxalate and the like. The term “pharmaceutically acceptable cation” refers to an acceptable cationic counter–ion of an acidic functional group. Such cations are exemplified by sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium cations, and the like. See, e.g., Berge, et al., J. Pharm. Sci. (1977) 66(1): 1–79. Methods of Use and Treatment [000124] Compounds described herein, e.g. compounds of Formula I, II, III, IV, V, VI, or subgenera thereof., are contemplated as S1PR4 receptor antagonists useful in the treatment of neurological, neurodegenerative, and cognitive disorders in subjects in need thereof. [000125] In another aspect, provided herein is a method of treating or preventing a neurological, neurodegenerative, or cognitive disorder, e.g., a neurological, neurodegenerative, or cognitive disorder described herein, in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. [000126] In another aspect, provided herein is a method of treating or preventing a lysosomal storage disorder, e.g., a lysosomal storage disorder described herein, in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. [000127] In another aspect, provided herein is a method of preventing a neurological, neurodegenerative, or cognitive disorder, e.g., a neurological, neurodegenerative, or cognitive disorder described herein, in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof [000128] In another aspect, provided herein is a method of treating a neurological, neurodegenerative, or cognitive disorder, e.g., a neurological, neurodegenerative, or cognitive disorder described herein, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof, or pharmaceutical composition thereof. [000129] In another aspect, provided herein is a method of treating a lysosomal storage disorder, e.g., a lysosomal storage disorder described herein, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. [000130] In some embodiments, exemplary disorders that can be treated by the compounds described herein, e.g., a compound of Formula I, II, III, IV, V, VI, or subgenera thereof., include but are not limited to: Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies, multiple system atrophy, Huntington's disease, lysosomal storage diseases including Gaucher, spinocerebellar ataxias (e.g., SCA1, SCA2, SCA3, SCA6, SCAT, and SCA17), spinobulbar muscular atrophy (SBMA) or Kennedy disease, dentatorubropallidoluysian atrophy (DRPLA), ALS, AIDS dementia, frontotemporal dementia, corticobasal ganglionic degeneration, progressive supranuclear palsy, Creutzfeldt-Jakob disease, Gerstmann- Sträussler-Scheinker syndrome, fatal familial insomnia, corticobasal ganglionic degeneration, hereditary spastic paraplegia, multiple sclerosis, neuromyelitis optica (Devic’s disease), concentric sclerosis (Baló’s disease), encephalomyelitis including acute disseminated encephalomyelitis (ADEM), acute haemorrhagic leucoencephalitis (AHL), Guillain-Barre Syndrome, chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis, Schilder’s disease, fibromyalgia, and optic neuritis; demyelination due to injury such as spinal cord injury, traumatic brain injury, cerebral palsy, neuropathy (e.g. neuropathy due to diabetes, chronic renal failure, hypothyroidism, liver failure, or compression of the nerve (e.g. in Bell's palsy) and post radiation injury; demyelination due to hypoxic-ischaemic events such as stroke, acute ischemic optic neuropathy, or other ischemia, and carbon monoxide exposure; demyelination due to metabolic disruption such as central pontine myelolysis (CPM) or extrapontine myelinolysis (EPM); demyelination due to inherited conditions such as Charcot-Marie-Tooth disease (CMT), Sjogren-Larsson syndrome, Refsum disease, Krabbe disease, Canavan disease, Alexander disease, Friedreich's ataxia, Pelizaeus-Merzbacher disease, Bassen-Kornzweig syndrome, metachromatic leukodystrophy (MLD), adrenoleukodystrophy, Leber’s optic neuropathy, and nerve damage due to pernicious anemia; demyelination due to a viral infection such as progressive multifocal leukoencephalopathy (PML), Lyme disease, tabes dorsalis due to untreated syphilis, HIV, or subacute sclerosing panencephalitis due to measles virus; demyelination due to toxic exposure such as chronic alcoholism (which is a possible cause of Marchiafava-Bignami disease), chemotherapy, mitochondrial toxins such as cyanide or hydrogen sulphide, or exposure to chemicals such as organophosphates; demyelination due to a dietary deficiency such as vitamin B12 deficiency, vitamin E deficiency and copper deficiency; or demyelination which has unknown causes or multiple causes such as trigeminal neuralgia, Marchiafava-Bignami disease, and Bell's palsy. [000131] Exemplary disorders that can be treated by the methods described herein include lysosomal storage diseases and related disorders. Accordingly, in some embodiments, exemplary disorders that can be treated by the compounds described herein, e.g., a compound of Formula I, II, III, IV, V, VI, or subgenera thereof, include but are not limited to lysosomal storage diseases, such as Activator deficiency, Alpha-mannosidosis, AB variant, Aspartylglucosaminuria, Batten–Spielmeyer–Vogt disease, Beta-galactosidase / GM1 gangliosidosis, Beta-mannosidosis, Chronic hexosaminidase A deficiency, cystinosis, CLN7 disease, Congenital cathepsin D deficiency, Cholesteryl ester storage disease, Cystinosis, Danon disease, Fabry disease, fucosidosis, I-cell disease, Krabbe disease, Farber disease, Finnish Variant, gangliosidosis, galactosialidosis, Gaucher disease (including type I, type II, and type III), GM2-AP deficiency, glycoprotein storage disorders, glucocerebroside, glycogen storage disease type II (pompe disease), GM2 gangliosidosis, German/Serbian late infantile, Hunter syndrome, Hurler syndrome, Hurler–Scheie syndrome, hyaluronidase deficiency, Infantile free sialic acid storage disease, Jansky–Bielschowsky disease, Juvenile hexosaminidase A deficiency, Late infantile variant, leukodystrophies, Kufs disease, lysosomal acid lipase deficiency, Maroteaux–Lamy syndrome, Metachromatic leukodystrophy, metachromatic leukodystrophy, Morquio syndrome, multiple sulfatase deficiency, multiple sulfatase deficiency, mucopolysaccharidoses, Mucolipidosis Type I (sialidosis), Mucolipidosis Type II (I-cell disease), Mucolipidosis Type III (pseudo-Hurler polydystrophy/phosphotransferase deficiency), Mucolipidosis Type IV (mucolipidin 1 deficiency), Niemann–Pick diseases, Neuronal ceroid lipofuscinoses, Northern epilepsy, Pycnodysostosis, Pompe disease, Salla disease, SAP deficiency, Sandhoff disease, saposin B deficiency, Sanfilippo syndrome, Santavuori–Haltia disease, Scheie syndrome, Schindler disease, Sly syndrome, Sphingolipidoses, sulfatidosis, Tay–Sachs disease, Turkish late infantile, variant AB, and Wolman disease. [000132] In an aspect, provided herein is a method of treating a neuroinflammatory disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, described herein is a method of preventing a neuroinflammatory disorder in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. [000133] In another aspect, provided herein is a method of treating neuroinflammation in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound described herein. In various embodiments, described herein is a method of preventing neuroinflammation in a subject in need thereof, the method comprising administering to the subject a prophylactically effective amount of a compound described herein. In some embodiments, the neuroinflammation is associated with a separate disorder in the subject.
[000134] Yet in another aspect, provided herein is a method of treating or preventing Corticobasal Degeneration, Progressive Supranuclear Paresis, Guillain-Barre Syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), viral encephalitis, cerebrovascular accidents, cranial trauma, Multiple Sclerosis is Relapse Remitting Multiple Sclerosis, Secondary Progressive Multiple Sclerosis, Primary Progressive Multiple Sclerosis, Legius syndrome, or demylation due to an exposure to a toxic substance in a subject in need thereof, comprising administering to the subject an effective amount of a compound described herein or a pharmaceutically acceptable salt thereof.
[000135] In one embodiment, described herein is a method of treating a genetic disorder resulting in loss-of-function in the ras signaling pathway in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In some embodiments, described herein is a method of preventing a genetic disorder resulting in loss-of-function in the ras signaling pathway in a subject in need thereof, comprising administering to the subject a prophylactically effective amount of a compound described herein or a pharmaceutically acceptable salt thereof. In embodiments, the genetic disorder resulting in loss-of-function in the ras signaling pathway is Legius syndrome.
Methods of Use and Treatment Definitions
[000136] Disease, disorder, and condition are used interchangeably herein.
[000137] As used herein, and unless otherwise specified, the terms “treat,” “treating” and “treatment” contemplate an action that occurs while a subject is suffering from the specified disease, disorder or condition, which reduces the severity of the disease, disorder or condition, or retards or slows the progression of the disease, disorder or condition .In an alternate embodiment, the present invention contemplates administration of the compounds of the present invention as a prophylactic before a subject begins to suffer from the specified disease, disorder or condition.. [000138] In general, the “effective amount” of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a CNS-related disorder, is sufficient to induce anesthesia or sedation. As will be appreciated by those of ordinary skill in this art, the effective amount of a compound of the invention may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses therapeutic and prophylactic treatment.
[000139] As used herein, and unless otherwise specified, a “therapeutically effective amount” of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder or condition, or to delay or minimize one or more symptoms associated with the disease, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment of the disease, disorder or condition. The term “therapeutically effective amount” can encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.
[000140] As used herein, and unless otherwise specified, a “prophylactically effective amount” of a compound is an amount sufficient to prevent a disease, disorder or condition, or one or more symptoms associated with the disease, disorder or condition, or prevent its recurrence. A prophylactically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other agents, which provides a prophylactic benefit in the prevention of the disease, disorder or condition. The term “prophylactically effective amount” can encompass an amount that improves overall prophylaxis or enhances the prophylactic efficacy of another prophylactic agent.
[000141] A “subject” to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g, young adult, middle-aged adult or senior adult)) and/or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In certain embodiments, the subject is a human. In certain embodiments, the subject is a non-human animal. Methods of Making General Synthetic scheme [000142] Exemplary methods for preparing compounds described herein are illustrated in the following synthetic schemes. These schemes are given for the purpose of illustrating the invention, and should not be regarded in any manner as limiting the scope or the spirit of the invention. [000143] In the schemes illustrated below, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 19 , and R 20 can be defined as described herein. In some exemplary procedures, R 6 is protected with a protecting group and then subsequently deprotected to provide the compound of Formula I, II, III, IV, V, or VI. [000144] The synthetic route illustrated in Scheme 1 depicts an exemplary procedure for preparing compound D. In the first step, compound A is hydrolyzed with lithium hydroxide monohydrate to form carboxylic acid B. Then, carboxylic acid B is reacted with amine C in the presence of HATU to provide compound D. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 1 [000145] The synthetic route illustrated in Scheme 2 depicts an exemplary procedure for preparing compound I. In the first step, compound E is reacted with hexamethylenetetramine to form F, which is consequently reacted with ethyl chlorooxoacetate to provide carbamate G. Then, phosphoryl chloride-mediated cyclization of G affords oxazole H. Peptide coupling of oxazole H with amine C in the presence of HATU provides compound I. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 2 [000146] The synthetic route illustrated in Scheme 3 depicts an exemplary procedure for preparing compound M. In the first step, compound J is reacted with 2,5-norbornadiene to form pyrazole carboxylate K. Then, pyrazole carboxylate K is hydrolyzed provide pyrazole carboxylic acid L. Peptide coupling of L with amine C in the presence of HATU provides compound M. In some exemplary procedures, R 6 of amine C is protected with a protecting group. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 3 [000147] The synthetic route illustrated in Scheme 4 depicts an exemplary procedure for preparing compound P. In this reaction, peptide coupling of amine N and carboxylic acid O in the presence of HATU provides compound P. In some exemplary procedures, R 6 of amine C is protected with a protecting group. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 4 [000148] The synthetic route illustrated in Scheme 5 depicts an exemplary procedure for preparing compound S. In the first step, compound Q is hydrolyzed with lithium hydroxide monohydrate to form carboxylic acid R. Then, peptide coupling of carboxylic acid R and amine C in the presence of HATU provides compound S. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 5 [000149] The synthetic route illustrated in Scheme 6 depicts an exemplary procedure for preparing compound S. In the first step, amine U is provided upon removal of carbamate from compound T. Then, amine U is reacted with isocyanate V to provide compound S. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 6 [000150] The synthetic route illustrated in Scheme 7 depicts an exemplary procedure for preparing compound D. In this reaction, carboxylic acid X is reacted with amine C to provide compound D. In some exemplary procedures, R 6 of amine C is protected with a protecting group. SCHEME 7 EXAMPLES [000151] In order that the invention described herein may be more fully understood, the following examples are set forth. The synthetic and biological examples described in this application are offered to illustrate the compounds, pharmaceutical compositions, and methods provided herein and are not to be construed in any way as limiting their scope. Materials and Methods [000152] The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization. [000153] All starting materials are commercially available from Sigma-Aldrich (including Fluka and Discovery CPR) or Acros unless otherwise noted after the chemical name. Reagent/reactant names given are as named on the commercial bottle or as generated by IUPAC conventions or ChemDraw 16.0. None of the specific conditions and reagents noted herein is to be construed as limiting the scope of the invention and are provided for illustrative purposes only. [000154] Additionally, as will be apparent to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesired reactions. The choice of a suitable protecting group for a particular functional group as well as suitable conditions for protection and deprotection are well known in the art. For example, numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Second Edition, Wiley, New York, 1991, and references cited therein. [000155] The compounds provided herein may be isolated and purified by known standard procedures. Such procedures include (but are not limited to) recrystallization, column chromatography, HPLC, or supercritical fluid chromatography (SFC). Analytical Methods [000156] Unless otherwise stated, all 1 H NMR data were collected on a Bruker Avance 400MHz equipped with 5mm QNP probe or Bruker Avance III 400MHz, 5mm BBFO plus probe instruments and chemical shifts are quoted in parts per million (ppm). LC/MS was performed on Acquity UPLC (binary pump/PDA detector) coupled to Waters ZQ Mass Spectrometer or Acquity i-Class (quaternary pump/PDA detector) coupled to Quattro Micro Mass Spectrometer or coupled to Waters DAD + Waters SQD2, single quadrapole UPLC- MS. LC/MS was also performed on an Agilent 1260 (binary pump/DAD detector) coupled to Agilent 6120 Mass Spectrometer. LC/MS data is referenced to LC/MS conditions using the method number provided in Table 2. Table 2. LC/MS analysis methods Purification Methods [000157] For the general procedures, intermediate and final compounds may be purified by any technique or combination of techniques known to one skilled in the art. Some examples that are not limiting include flash chromatography with a solid phase (silica gel, alumina, etc.) and a solvent (or combination of solvents (heptane, EtOAc, DCM, MeOH, MeCN, water, etc.) that elutes the desired compounds; RP-HPLC purification performed on Agilent Technologies 1260 Infinity purification system, Agilent 6120 series Single Quadrupole Mass Spectrometer, Gilson purification system (306 pump and GX-281 fraction collector), Shimadzu LC20Ap and Waters MS triggered purification system (see Table 2 for some non- limiting conditions); recrystallization from an appropriate solvent (MeOH, EtOH, i-PrOH, EtOAc, toluene, etc.) or combination of solvents (EtOAc/heptane, EtOAc/MeOH, etc.); precipitation from a combination of solvents (DMF/water, DMSO/DCM, EtOAc/heptane, etc.); trituration with an appropriate solvent (EtOAc, DCM, MeCN, MeOH, EtOH, i-PrOH, n-PrOH, etc.); extractions by dissolving a compound in a liquid and washing with an appropriately immiscible liquid (DCM/water, EtOAc/water, DCM/saturated NaHCO 3 , EtOAc/saturated NaHCO 3 , DCM/10% aqueous HCl, EtOAc/10% aqueous HCl, etc.); distillation (simple, fractional, Kugelrohr, etc.). Descriptions of these techniques can be found in the following references: Gordon, A. J. and Ford, R. A. "The Chemist’s Companion”, 1972; Palleros, D. R. “Experimental Organic Chemistry”, 2000; Still, W. C., Kahn and M. Mitra, A. J. Org. Chem.1978, 43(14), 2923-2925; Yan, B. “Analysis and Purification Methods in Combinatorial Chemistry” 2003; Harwood, L. M., Moody, C. J. and Percy, J. M. “Experimental Organic Chemistry: Standard and Microscale, 2 nd Edition”, 1999. Table 3. RP-HPLC purification methods
Abbreviations [000158] ACN or MeCN: acetonitrile; DAD: dimethylacetamide; DIEA: N,N- diisopropylethylamine; DIPEA: N,N-diisopropylethylamine; DMF: dimethylformamide; DMSO: dimethyl sulfoxide; EA or EtOAc: ethyl acetate; EDG6: endothelial differentiation G-protein coupled receptor 6; ESI: electrospray ionization; DCM: dichloromethane; MeOH: methanol; HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyri dinium 3- oxide hexafluorophosphate; HPLC: high-performance liquid chromatography; i-PrOH: isopropyl alcohol; Ir[dF(CF 3 )ppy](dtbbpy)PF 6 : [4,4′-Bis(1,1-dimethylethyl)-2,2′-bipyridine- N1,N1′]bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl -N]phenyl-C]Iridium(III) hexafluorophosphate; LC/MS: liquid chromatography–mass spectrometry; LED: light- emitting diode; MDAP: Mass Directed Auto Purification; NMR: Nuclear Magnetic Resonance; n-PrOH: propanol; PDA: polydiacetylenes; PE: petroleum ether; QNP: quadruple probe; RT: room temperature; S1PR4: sphingosine 1-phosphate receptor 4; SFC: supercritical fluid chromatography; SQD2: single quadrupole detection; THF: tetrahydrofuran; TLC: thin- layer chemistry; UPLC: ultra-performance liquid chromatography; Xphos: 2- dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl. Example 1.2-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)oxazole-5- carboxamide (i) Ethyl 2-(2,5-dichlorophenyl)oxazole-5-carboxylate [000159] A reaction vessel was charged ethyl 2-bromooxazole-5-carboxylate (100 mg, 0.455 mmol), 2,5-dichlorophenylboronic acid (104 mg, 0.545 mmol), tetrakis(triphenylphosphine)palladium(0) (53 mg, 0.0455 mmol), cesium carbonate (222 mg, 0.682 mmol) and solvated in 1,4-dioxane (3.0 mL) and distilled water (0.5 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 100 ºC. The reaction was heated at 100ºC for 18 h. The reaction was allowed to cool to RT and next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 80 : 20, gradient elution) to afford the title product (58 mg, 45%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.22 (s, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.73 - 7.72 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.33 (dd, J = 7.1, 7.1 Hz, 3H). (ii) 2-(2,5-Dichlorophenyl)oxazole-5-carboxylic acid [000160] To a suspension of ethyl 2-(2,5-dichlorophenyl)oxazole-5-carboxylate (58 mg, 0.203 mmol) in methanol (2.0 mL) and distilled water (0.5 mL) was added lithium hydroxide monohydrate (13 mg, 0.304 mmol). The reaction was set to stir at RT and next warmed to 45 ºC. The reaction was heated at 45 ºC for 1.5 h. The reaction was allowed to cool to RT and the organics were removed in vacuo. The aqueous layer was acidified with 1N HCl to pH ~3 and the resulting precipitate filtered and dried in vacuo to afford the title compound (45 mg, 87%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.10 (s, 1H), 8.05 (d, J = 2.3 Hz, 1H), 7.73 - 7.70 (m, 2H) and one exchangeable proton. (iii) 2-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)oxazole-5- carboxamide. [000161] A reaction vessel was charged with 2-(2,5-dichlorophenyl)oxazole-5-carboxylic acid (45 mg, 0.174 mmol), (4-amino-3,5-dimethylphenyl)methanol (Preparation 1, 32 mg, 0.209 mmol), HATU (93 mg, 0.244 mmol) and solvated in DMF (2.0 mL). Triethylamine (49 µL, 0.349 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 0.5 h. The reaction was next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate 90 : 10, gradient elution) to afford the title compound as a white solid (21 mg, 30%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.37 (d, J = 2.5 Hz, 1H), 8.12 (s, 1H), 7.75 - 7.67 (m, 2H), 7.09 (s, 2H), 5.16 (dd, J = 5.7, 5.7 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 2.20 (s, 6H). LC/MS (Table 2, Method A) Rt = 4.43 mins; MS m/z: 391/333 [M+H] + . Example 2.5-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)oxazole-2- carboxamide (i) 2-Bromo-1-(2,5-dichlorophenyl)ethan-1-one [000162] A reaction vessel was charged with 2,5-dichloroacetophenone (3.8 mL, 26.45 mmol) and solvated in DCM (100 mL). The reaction was set to stir at RT and next cooled to 0 ºC. Bromine (1.4 mL, 27.77 mmol) as a solution in DCM (50 mL) was added dropwise. The reaction was stirred at 0 ºC for 2 h. The reaction was next partitioned between DCM and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by flash column chromatography (cyclohexane to cyclohexane : DCM, 50 : 50, gradient elution) to afford the title compound (5.2 g, 73%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.52 (d, J = 2.1 Hz, 1H), 7.44 - 7.36 (m, 2H), 4.49 (s, 2H). (ii) 2-Amino-1-(2,5-dichlorophenyl)ethan-1-one [000163] To a solution of 2-bromo-1-(2,5-dichlorophenyl)ethan-1-one (2.5 g, 9.33 mmol) in chloroform (50 mL) was added hexamethylenetetramine (1.31 g, 9.33 mmol) and the reaction was set to stir at RT. The reaction was stirred at RT for 2 h. A white precipitate formed which was collected by filtration in vacuo and resuspended in a mixture of industrial methylated spirit (20 mL), concentrated hydrochloric acid (2 mL) and distilled water (2 mL). The reaction was stirred at RT for 24 h and filtered in vacuo to give a white solid. The solid was further triturated with warm IPA, filtered and dried in vacuo to afford the title compound as a white solid (619 mg, 81%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.39 (s, 2H), 8.05 (d, J = 2.4 Hz, 1H), 7.74 (dd, J = 2.5, 8.6 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 4.55 (s, 2H). (iii) Ethyl 2-((2-(2,5-dichlorophenyl)-2-oxoethyl)amino)-2-oxoacetate [000164] To a solution of 2-amino-1-(2,5-dichlorophenyl)ethan-1-one (619 mg, 2.57 mmol) in THF was added ethyl chlorooxoacetate (400 µL, 3.60 mmol) and triethylamine (900 µL, 6.43 mmol). The reaction as set to stir at RT. The reaction was stirred at RT for 24 h. The reaction was next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to ethyl acetate, gradient elution) to afford the title compound (474 mg, 61%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.89 (s, 1H), 7.66 (d, J = 2.3 Hz, 1H), 7.47 - 7.40 (m, 2H), 4.77 (d, J = 5.2 Hz, 2H), 4.40 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.3 Hz, 3H). (iv) Ethyl 5-(2,5-dichlorophenyl)oxazole-2-carboxylate [000165] To a solution of ethyl 2-((2-(2,5-dichlorophenyl)-2-oxoethyl)amino)-2-oxoacetate (474 mg, 1.56 mmol) in toluene (5.0 mL) was added phosphorus (V) oxychloride (580 µL, 6.23 mmol). The reaction was set to stir at RT and next warmed to reflux. The reaction was heated at reflux for 26.5 h. The reaction was allowed to cool to RT. The reaction was next diluted with distilled water and partitioned with ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title compound (202 mg, 45%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.95 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.32 (dd, J = 2.5, 8.6 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.2 Hz, 3H). (v) 5-(2,5-Dichlorophenyl)oxazole-2-carboxylic acid [000166] To a suspension of ethyl 5-(2,5-dichlorophenyl)oxazole-2-carboxylate (202 mg, 0.706 mmol) in methanol (5.0 mL) and distilled water (1.0 mL) was added lithium hydroxide monohydrate (44 mg, 1.06 mmol). The reaction was set to stir at RT and next warmed to 50 ºC. The reaction was heated at 50 ºC for 1 h. The reaction was allowed to cool to RT and the organics were removed in vacuo. The aqueous layer was acidified with 1N hydrochloric acid to pH ~4 and the resulting precipitate filtered and dried in vacuo to afford the title compound as an off-white solid (167 mg, 92%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.06 (s, 1H), 7.86 (dd, J = 2.9, 2.9 Hz, 1H), 7.70 (d, J = 8.7 Hz, 1H), 7.58 (dd, J = 2.6, 8.6 Hz, 1H) and one exchangeable proton. (vi) 5-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)oxazole-2- carboxamide [000167] A reaction vessel was charged with 5-(2,5-dichlorophenyl)oxazole-2-carboxylic acid (90 mg, 0.349 mmol), (4-amino-3,5-dimethylphenyl)methanol (Preparation 1, 63 mg, 0.419 mmol), HATU (186 mg, 0.488 mmol) and solvated in DMF (5 mL). Triethylamine (97 µL, 0.698 mmol) was added and the reaction was stirred at RT for 1 h. The reaction was next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Method 1) to afford the title compound as a white solid (28 mg, 21%). LC/MS (Table 2, Method B) R t = 4.77 min; MS m/z: 391/393 [M+H] + . Example 3.2-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)isonicotinamide (i) Methyl 2-(2,5-dichlorophenyl)isonicotinate [000168] A reaction vessel was charged with methyl 2-bromopyrimidine-4-carboxylate (566 mg, 2.62 mmol), 2,5-dichlorophenylboronic acid (500 mg, 2.62 mmol), tetrakis(tripenylphosphine)palladium(0) (303 mg, 0.262 mmol), cesium carbonate (2.56 g, 7.86 mmol) and solvated in 1,4-dioxane (10.0 mL) and distilled water (2.0 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 ºC. The reaction was heated at 80 ºC for 1 h. The reaction was allowed to cool to RT and next partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title compound (520 mg, 70%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.88 (d, J = 5.0 Hz, 1H), 8.22 (s, 1H), 7.87 (dd, J = 1.4, 5.0 Hz, 1H), 7.63 (d, J = 2.5 Hz, 1H), 7.44 (d, J = 8.6 Hz, 1H), 7.34 (dd, J = 2.5, 8.5 Hz, 1H), 3.99 (s, 3H). (ii) 2-(2,5-Dichlorophenyl)isonicotinic acid [000169] To a solution of methyl 2-(2,5-dichlorophenyl)isonicotinate (450 mg, 1.60 mmol) in 1,4-dioxane (4.0 mL) was added lithium hydroxide monohydrate (268 mg, 6.38 mmol) in distilled water (4.0 mL). The reaction was set to stir at RT and warmed to 50 ºC. The reaction was heated at 50 ºC for 1 h. The reaction was allowed to cool to RT and the organics were removed in vacuo. The aqueous layer was acidified with 1N hydrochloric acid to pH =1 and the resulting precipitate filtered and dried in vacuo to afford the title compound (330 mg, 77%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 8.90 (d, J = 4.9 Hz, 1H), 8.10 (s, 1H), 7.89 (dd, J = 1.5, 5.0 Hz, 1H), 7.71 (d, J = 2.3 Hz, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.60 - 7.55 (m, 1H) and one exchangeable proton. (iii) 2-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)isonicotinamide [000170] A reaction vessel was charged with 2-(2,5-dichlorophenyl)isonicotinic acid (89 mg, 0.331 mmol) (4-amino-3,5-dimethylphenyl)methanol (Preparation 1, 50 mg, 0.331 mmol), HATU (176 mg, 0.463 mmol) and solvated in DMF (2.0 mL). DIPEA (172 µL 0.992 mmol) was added and the reaction was set to stir at RT for 18 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography followed by reverse phase HPLC (Method 2) to afford the title compound as a white solid (15 mg, 11%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.09 (s, 1H), 8.91 (d, J = 5.1 Hz, 1H), 8.19 (s, 1H), 7.97 (dd, J = 1.6, 5.1 Hz, 1H), 7.75 (d, J = 2.5 Hz, 1H), 7.67 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 2.6, 8.6 Hz, 1H), 7.08 (s, 2H), 4.46 (s, 2H), 2.18 (s, 6H) and one exchangeable proton. LC/MS (Table 2, Method B) R t = 4.45 min; MS m/z: 401/403 [M+H] + . Example 4.5-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)nicotinamide (i) Ethyl 5-(2,5-dichlorophenyl)nicotinate [000171] A reaction vessel was charged with ethyl 5-bromonicotinate (603 mg, 2.62 mmol), 2,5-dichlorophenylboronic acid (500 mg, 2.62 mmol), tetrakis(triphenylphosphine)palladium(0) (303 mg, 0.262 mmol), cesium carbonate (2.56 g, 7.86 mmol) and solvated in 1,4-dioxane (10.0 mL) and distilled water (2.0 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 ºC. The reaction was heated at 80 ºC for 1.5 h. The reaction was allowed to cool to RT and partitioned between distilled water and ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to diethyl ether, gradient elution) to afford the title compound (740 mg, 95%). ¹H NMR (400 MHz, CDCl 3 ) δ 9.26 (d, J = 1.9 Hz, 1H), 8.84 (d, J = 2.0 Hz, 1H), 8.37 (dd, J = 2.0, 2.0 Hz, 1H), 7.46 (d, J = 9.1 Hz, 1H), 7.36 (d, J = 7.2 Hz, 2H), 4.45 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.3 Hz, 3H). (ii) 5-(2,5-Dichlorophenyl)nicotinic acid [000172] To a solution of ethyl 5-(2,5-dichlorophenyl)nicotinate (740 mg, 2.5 mmol) in 1,4- dioxane (10.0 mL) and methanol (1.0 mL) was added lithium hydroxide monohydrate in distilled water (5.0 mL). The reaction was set to stir at RT and next heated at 50 ºC for 0.5 h. The reaction was allowed to cool to RT and the organics were removed in vacuo. The aqueous layer was acidified with 1N hydrochloric acid to pH ~6 and the resulting precipitate filtered and dried in vacuo to afford the title compound (240 mg, 36%). ¹H NMR (400 MHz, DMSO- d 6 ) δ 9.05 (d, J = 1.4 Hz, 1H), 8.69 (d, J = 2.0 Hz, 1H), 8.24 (dd, J = 2.1, 2.1 Hz, 1H), 7.68 - 7.62 (m, 2H), 7.54 (dd, J = 2.6, 8.6 Hz, 1H) and one exchangeable proton. (iii) 5-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)nicotinamide [000173] A reaction vessel was charged with 5-(2,5-dichlorophenyl)nicotinic acid (89 mg, 0.331 mmol), (4-amino-3,5-dimethylphenyl)methanol (Preparation 1, 50 mg, 0.331 mmol), HATU (176 mg, 0.463 mmol) and solvated in DMF (2.0 mL). DIPEA (172 µL, 0.992 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 3 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified by reverse phase HPLC (Method 2) to afford the title compound as a white solid (15 mg, 11%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.02 - 9.99 (m, 1H), 9.20 (d, J = 2.0 Hz, 1H), 8.89 (d, J = 2.1 Hz, 1H), 8.43 (dd, J = 2.1, 2.1 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.70 (d, J = 8.6 Hz, 1H), 7.59 (dd, J = 2.6, 8.6 Hz, 1H), 7.08 (s, 2H), 5.16 (dd, J = 5.7, 5.7 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 2.20 (s, 6H). LC/MS (Table 2, Method C) R t = 4.40 min; MS m/z: 401/403 [M+H] + . Example 5.4-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)picolinamide (i) Methyl 4-(2,5-dichlorophenyl)picolinate [000174] A reaction vessel was charged with methyl 4-bromopicolinate (566 mg, 2.62 mmol), 2,5-dichlorophenylboronic acid (500 mg, 2.62 mmol), tetrakis(triphenylphosphine\)palladium (0) (303 mg, 0.262 mmol), cesium carbonate (2.56 g, 7.86 mmol) and solvated in 1,4-dioxane (10 mL) and distilled water (2.0 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 ºC. The reaction was heated at 80 ºC for 1.5 h. The reaction was stopped and allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to tert-butyl methyl ether gradient elution) to afford the title compound as a white solid (170 mg, 23%). ¹H NMR (400 MHz, CDCl 3 ) δ 8.83 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 1.2 Hz, 1H), 7.57 (dd, J = 1.8, 4.9 Hz, 1H), 7.46 (d, J = 9.3 Hz, 1H), 7.39 - 7.36 (m, 2H), 4.04 (s, 3H). (ii) 4-(2,5-Dichlorophenyl)picolinic acid [000175] A reaction vessel was charged with methyl 4-(2,5-dichlorophenyl)picolinate (170 mg, 0.603 mmol) and dissolved in 1,4-dioxane (3.0 mL) and distilled water (1.5 mL). Next, lithium hydroxide monohydrate (101 mg, 2.41 mmol) was added. The reaction was set to stir at RT and next warmed to 50 ºC. The reaction was heated at 50 ºC for 0.5 h. The reaction was allowed to cool to RT and the organics removed in vacuo. The aqueous layer was acidified with 1N hydrochloric acid to pH ~7 and the resulting precipitate filtered and dried in vacuo to afford the title compound as a white solid (89 mg, 55%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.82 (d, J = 4.9Hz, 1H), 8.10 (s, 1H), 7.75 (dd, J = 1.5, 4.9Hz, 1H), 7.70 - 7.65 (m, 2H), 7.62 - 7.56 (m, 1H) and one exchangeable proton. (iii) N-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)picolinamide [000176] A reaction vessel was charged with 4-(2,5-dichlorophenyl)picolinic acid (85 mg, 0.317 mmol, ((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylaniline (Preparation 2, 65 mg, 0.245 mmol), HATU (169 mg, 0.444 mmol) and solvated in DMF (2 mL). DIPEA (170 µL, 0.951 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 0.5 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 70 : 30, gradient elution ) to afford the title compound as an off-white solid (126 mg, 40%). ¹H NMR (400 MHz, CDCl 3 ) δ 9.36 - 9.32 (m, 1H), 8.59 (d, J = 4.9 Hz, 1H), 8.23 - 8.22 (m, 1H), 7.48 (dd, J = 1.7, 5.0 Hz, 1H), 7.36 - 7.21 (m, 2H), 7.14 (s, 1H), 6.97 (s, 2H), 4.58 (s, 2H), 2.19 (s, 6H), 1.31 (s, 6H), 0.84 (s, 9H). (iv) 4-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)picolinamide [000177] A reaction vessel was charged with N-(4-(((tert-butyldimethylsilyl)oxy)methyl)- 2,6-dimethylphenyl)-4-(2,5-dichlorophenyl)picolinamide (48 mg, 0.0931 mmol) and solvated in THF (2 mL). Next, tetrabutylammonium fluoride solution (32 mL, 0.12 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 1.5 h. The reaction was next partitioned between ethyl acetate and sodium hydrogen carbonate. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by flash column chromatography (DCM to DCM : MeOH, 95 : 5, gradient elution) to afford the title compound as a white solid (37 mg, quant.). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 8.85 (d, J = 5.1 Hz, 1H), 8.15 - 8.14 (m, 1H), 7.79 (dd, J = 1.8, 5.0 Hz, 1H), 7.71 - 7.68 (m, 2H), 7.60 (dd, J = 2.6, 8.6 Hz, 1H), 7.06 (s, 2H), 5.13 (dd, J = 5.7, 5.7 Hz, 1H), 4.45 (d, J = 5.6 Hz, 2H), 2.18 (s, 6H). LC/MS (Table 2, Method A) R t = 5.12 min; MS m/z: 401/403 [M+H] + . Example 6.4-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)thiazole-2- carboxamide (i) Ethyl 4-(2,5-dichlorophenyl)thiazole-2-carboxylate [000178] A reaction vessel was charged with 2,5-dichlorothiobenzamide (1.0 g, 4.85 mmol), ethyl bromopyruvate (2.52 g, 9.70 mmol), pyridine (1.15 g, 14.56 mmol) and solvated in ethanol (9.7 mL). The reaction was set to stir art RT and next warmed to 150 ºC in a microwave reactor. The reaction was heated at 150 ºC under microwave irradiation for 1.5 h. The reaction was allowed to cool to RT and next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 90 : 10, gradient elution) to afford the title compound (254 mg, 17%).¹H NMR (400 MHz, CDCl 3 ) δ 8.14 (s, 1H), 8.02 (d, J = 2.6 Hz, 1H), 7.41 (d, J = 8.5 Hz, 1H), 7.28 (dd, J = 2.6, 8.6 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 1.47 (t, J = 7.5 Hz, 3H). (ii) 4-(2,5-Dichlorophenyl)thiazole-2-carboxylic acid [000179] To a solution of ethyl 4-(2,5-dichlorophenyl)thiazole-2-carboxylate (254 mg, 0.841 mmol) in methanol (6.3 mL) was added lithium hydroxide monohydrate (74 mg, 1.77 mmol) in distilled water (2.1 mL). This reaction was stirred at RT for 2 h. The reaction was partitioned between diethyl ether and distilled water. The aqueous layer was separated and acidified to pH~2 with 1N HCl solution. This aqueous layer was again partitioned with ethyl acetate. The ethyl acetate layer was separated and the combined organics, dried (MgSO 4 ) and concentrated in vacuo to afford the title compound as a white solid (200 mg, 87%). ¹H NMR (400 MHz, CDCl 3 ) δ 8.27 (s, 1H), 7.96 (d, J = 2.6 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H), 7.32 (dd, J = 2.6, 8.5 Hz, 1H) and one exchangeable proton. (iii) 4-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)thiazole-2-carboxamide [000180] A reaction vessel was charged with 4-(2,5-dichlorophenyl)thiazole-2-carboxylic acid (75 mg, 0.274 mmol), (4-amino-3,5-dimethylphenyl)methanol (50 mg, 0.328 mmol), HATU (135 mg, 0.356 mmol) and solvated in DMF (3.0 mL). Triethylamine (55 mg, 0.547 mmol) was added and the reaction set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude product was further purified by reverse phase HPLC (Method 3) to afford the title compound as a white powder (23 mg, 21%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 8.61 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.66 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = 2.6, 8.6 Hz, 1H), 7.09 (s, 2H), 5.16 (dd, J = 5.7, 5.7 Hz, 1H), 4.47 (d, J = 5.6 Hz, 2H), 2.21 (s, 6H). LC/MS (Table 2, Method D) R t = 5.38 min; MS m/z: 407/409 [M+H] + . Example 7.2-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)thiazole-4- carboxamide. (i) Methyl 2-(2,5-dichlorophenyl)thiazole-4-carboxylate [000181] A reaction vessel was charged with methyl 2-bromothiazole-4-carboxylate (582 mg, 2.62 mmol), 2,5-dichlorophenylboronic acid (500 mg, 2.62 mmol), tetrakis(triphenylphosphine)palladium(0), cesium carbonate (2.56 g, 7.86 mmol) and solvated in 1,4-dioxane (10.0 mL) and distilled water (2.0 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 ºC. The reaction was heated at 80 ºC for 1 h. The reaction was allowed to cool to RT and next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title product (270 mg, 35%). ¹H NMR (400 MHz, CDCl 3 ) δ 8.34 (s, 2H), 7.44 (d, J = 8.6 Hz, 1H), 7.35 (dd, J = 2.5, 8.6 Hz, 1H), 4.00 (s, 3H). (ii) 2-(2,5-Dichlorophenyl)thiazole-4-carboxylic acid [000182] To a solution of methyl 2-(2,5-dichlorophenyl)thiazole-4-carboxylate (210 mg, 0.729 mmol) in 1,4-dioxane (4.0 mL) was added lithium hydroxide monohydrate (122 mg, 2.92 mmol) in distilled water (4.0 mL). The reaction was set to stir at RT and next warmed to 50 ºC. The reaction was heated at 50 ºC for 1 h. This reaction was allowed to cool to RT and the organics removed in vacuo. The aqueous layer was acidified to pH~1 with 1N HCl and the resulting precipitate filtered and dried in vacuo to afford the title compound as a white solid (170 mg, 85%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 13.26 (s, 1H), 8.69 (s, 1H), 8.25 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.64 (dd, J = 2.6, 8.6 Hz, 1H). (iii) N-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-2-(2,5- dichlorophenyl)thiazole-4-carboxamide [000183] A reaction vessel was charged with 2-(2,5-dichlorophenyl)thiazole-4-carboxylic acid (75 mg, 0.274 mmol), 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylaniline (Preparation 2, 80 mg, 0.301 mmol), HATU (146 mg, 0.383 mmol) and solvated in DMF (2.0 mL). DIPEA (143 µL 0.821 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to diethyl ether, gradient elution) to afford the title product (60 mg, 42%). ¹H NMR (400 MHz, CDCl 3 ) δ 8.63 (s, 1H), 8.26 (s, 1H), 8.17 (d, J = 2.5 Hz, 1H), 7.37 (d, J = 8.6 Hz, 1H), 7.26 (dd, J = 2.6, 8.5 Hz, 1H), 6.97 (s, 2H), 4.59 (s, 2H), 2.20 (s, 6H), 0.84 (s, 9H), 0.00 (s, 6H). (iv) 2-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)thiazole-4- carboxamide [000184] To a solution of N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)- 2-(2,5-dichlorophenyl)thiazole-4-carboxamide (60 mg, 0.15 mmol) in THF (2.0 mL) was added tetrabutylammonium fluoride (1N in THF, 140 µL) and the reaction was set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was next partitioned between ethyl acetate and sodium hydrogen carbonate. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by flash column chromatography (DCM to DCM : MeOH, 19 : 1, gradient elution) to afford the title compound (33 mg, 70%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.15 (s, 1H), 8.85 (d, J = 2.6 Hz, 1H), 8.59 (s, 1H), 7.73 (d, J = 8.7 Hz, 1H), 7.62 (dd, J = 2.6, 8.6 Hz, 1H), 7.09 (s, 2H), 5.16 (dd, J = 5.7, 5.7 Hz, 1H), 4.47 (d, J = 5.7 Hz, 2H), 2.20 (s, 6H). LC/MS (Table 2, Method A) R t = 5.15 min; MS m/z: 407/409 [M+H] + . Example 8.1-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylph enyl)-1H-pyrazole- 3-carboxamide (i) Ethyl (Z)-2-chloro-2-(2-(2,5-dichlorophenyl)hydrazineylidene)aceta te [000185] To a suspension of 2,5-dichloroaniline (3.0 g, 18.52 mmol) in distilled water (100 mL) was added hydrochloric acid (12N, 4.6 mL, 55.55 mmol). The reaction was set to stir at RT and next cooled to 0 ºC Sodium nitrite (1.41 g, 20.37 mmol) in distilled water (3.0 mL) was added dropwise at 0 ºC. This reaction was stirred at 0 ºC for 0.5 h. Next, ethyl 2- chloroacetoacetate (3.36 g, 2.82 mL, 20.37 mmol) and sodium acetate (3.03 g, 37.04 mmol) were added at 0 ºC. The reaction was allowed to warm to RT and stirred at RT for 1.5 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude product was triturated in MeOH to afford the title compound as a pale orange solid (2.7 g, 50%). ¹H NMR (400 MHz, CDCl 3 ) δ 8.75 (s, 1H), 7.63 (d, J = 2.4 Hz, 1H), 7.27 (d, J = 8.6 Hz, 1H), 6.95 (dd, J = 2.4, 8.5 Hz, 1H), 4.42 (q, J = 7.2 Hz, 2H), 1.42 (t, J = 7.2 Hz, 3H). (ii) Ethyl 1-(2,5-dichlorophenyl)-1H-pyrazole-3-carboxylate [000186] A reaction vessel was charged with ethyl (Z)-2-chloro-2-(2-(2,5- dichlorophenyl)hydrazineylidene)acetate (1.09 g,3.69 mmol), bicyclo[2.2.1]hepta-2,5-diene (1.35 g, 14.75 mmol), triethylamine (1.08 g, 10.69 mmol) and further solvated in xylene (7.0 mL). The reaction was set to stir at RT and next allowed to warm to 140 ºC. The reaction was heated at 140 ºC for 1 h. The reaction was allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to ethyl acetate : cyclohexane, 70 : 30, gradient elution) to afford the title product (770 mg, 73%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.89 (d, J = 2.5 Hz, 1H), 7.69 (d, J = 2.4 Hz, 1H), 7.46 (d, J = 8.6 Hz, 1H), 7.36 (dd, J = 2.4, 8.6 Hz, 1H), 7.01 (d, J = 2.5 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.43 (t, J = 7.1 Hz, 3H). (iii) 1-(2,5-Dichlorophenyl)-1H-pyrazole-3-carboxylic acid [000187] To a solution of ethyl 1-(2,5-dichlorophenyl)-1H-pyrazole-3-carboxylate (770 mg, 2.70 mmol) in MeOH (10.0 mL) was added lithium hydroxide hydrate (170 mg, 4.05 mmol) in distilled water (1.0 mL). The reaction was set to stir at RT and next heated at 50 ºC for 1 h. The reaction was allowed to cool to RT and the organics removed in vacuo. The aqueous layer was acidified to pH~4 with 1N HCl and the resulting precipitate filtered and dried in vacuo to afford the title compound (646 mg, 93%).¹H NMR (400 MHz, DMSO-d 6 ) δ 13.02 (s, 1H), 8.27 (d, J = 2.5 Hz, 1H), 7.82 (d, J = 2.5 Hz, 1H), 7.77 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 2.5, 8.7 Hz, 1H), 6.95 (d, J = 2.5 Hz, 1H). (iv) 1-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)-1H-pyrazole-3- carboxamide [000188] A reaction vessel was charged with 1-(2,5-dichlorophenyl)-1H-pyrazole-3- carboxylic acid (150 mg, 0.583 mmol), (4-amino-3,5-dimethylphenyl)methanol (Preparation 1, 106 mg, 0.700 mmol), HATU (311 mg, 0.817 mmol) and solvated in DMF (5.0 mL). Triethylamine (161 µL, 1.17 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 18 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (DCM to DCM : MeOH, 90 : 10, gradient elution) to afford the title product (62 mg, 27%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 9.69 (s, 1H), 8.34 (d, J = 2.6 Hz, 1H), 7.95 (d, J = 2.5 Hz, 1H), 7.78 (d, J = 8.7 Hz, 1H), 7.66 (dd, J = 2.6, 8.7 Hz, 1H), 7.04 (s, 2H), 7.00 (d, J = 2.6 Hz, 1H), 5.12 (dd, J = 5.7, 5.7 Hz, 1H), 4.44 (d, J = 5.7 Hz, 2H), 2.17 (s, 6H). LC/MS (Table 2, Method A) R t = 4.50 min; MS m/z: 390/392 [M+H] + . Example 9. N-(2',5'-Dichloro-[1,1'-biphenyl]-3-yl)-4-(hydroxymethyl)-2, 6- dimethylbenzamide (i) 2',5'-Dichloro-[1,1'-biphenyl]-3-amine [000189] A reaction vessel was charged with 3-bromoaniline (7.5 g, 44.0 mmol), (2,5-dichlorophenyl)boranediol (10.0 g, 50.0 mmol), potassium carbonate (12.0 g, 80.0 mmol), tetrakis(triphenylphosphine)palladium(0) (10.0 g, 8.70 mmol) and solvated in 1,4- dioxane (100 mL) and distilled water (10 mL). The reaction was degassed and placed under an argon. The reaction was set to stir at RT and next warmed to 90 ºC. The reaction was heated at 90 ºC for 10 h. The reaction was allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 80 : 20, gradient elution) to give the title compound as a yellow oil (8.5 g, 81%). LC/MS (Table 2, Method E) R t = 1.48 min; MS m/z: 237.9 [M+H] + . (ii) Ethyl 4-amino-3,5-dimethylbenzoate [000190] To a solution of 4-bromo-2,6-dimethylaniline (10.0 g, 0.05 mol) and triethylamine (13.7 mL, 0.1 mol) in EtOH (50 mL) was added bis(triphenylphosphine)palladium(II) chloride (7.0 g, 0.01 mol) under a carbon monoxide atmosphere at 25 ºC (1 MPa). The reaction was stirred at RT and next warmed 130 ºC. The reaction was heated at 130 ºC for 8 h. The reaction was next allowed to cool to RT. The reaction was concentrated in vacuo to give a yellow oil and the crude material was purified directly by flash column chromatography (petroleum ether 40-60 ºC to petroleum ether 40-60 ºC : ethyl acetate, 50 : 50, gradient elution) to afford the title product (9.3 g, 95%). LC/MS (Table 2, Method E) R t = 1.48 min; MS m/z: 193.9 [M+H] + . (iii) Ethyl 4-bromo-3,5-dimethylbenzoate [000191] A reaction vessel was charged with ethyl 4-amino-3,5-dimethylbenzoate (4.0 g, 0.02 mol) in hydrogen bromide (48% in H 2 O, 50 mL) and set to stir at RT. The reaction was cooled to 0 ºC and a solution of sodium nitrite (4.3 g, 60.0 mmol) in distilled water (20 mL) was added dropwise over 0.5 h at 0 ºC. The reaction was stirred at 0 ºC for an additional 10 min. Bromine (5.0 g, 30.0 mmol) was next added and the reaction was stirred for an additional 1 h at 0 ºC. The reaction was adjusted to pH~8 with saturated sodium hydrogen carbonate and partitioned with ethyl acetate. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo to give black oil. The crude material was purified by flash column chromatography (petroleum ether 40-60 ºC to petroleum ether 40-60 ºC : ethyl acetate, 80 : 20, gradient elution) to afford the title compound as a yellow solid (1.5 g, 28%). LC/MS (Table 2, Method E) R t = 1.81 min; MS m/z: 256.8/258.8 [M+H] + . (iv) (4-Bromo-3,5-dimethylphenyl)methanol [000192] A reaction vessel was charged with ethyl 4-bromo-3,5-dimethylbenzoate (1.5 g, 5.8 mmol) and solvated in THF (50.0 mL). The reaction was set to stir at RT and next cooled to 0 ºC. Lithium aluminum hydride (1M in THF, 17.4 mL, 17.4 mmol) was added dropwise at 0 ºC and the reaction was next allowed to warm to RT. The reaction was stirred at RT for 3 h. The reaction was next cooled to 0 ºC, cautiously quenched with distilled water and filtered in vacuo. The filtrate was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo to give an oil. The crude material was purified by flash column chromatography (petroleum ether 40-60 ºC to petroleum ether 40-60 ºC : ethyl acetate, 50 : 50, gradient elution) to give the title compound as a pale oil (800 mg, 64%). LC/MS (Table 2, Method E) R t = 1.54 min; MS m/z: 196.9/198.8 [M+H] + . (v) 4-(Hydroxymethyl)-2,6-dimethylbenzoic acid [000193] A reaction vessel was charged with 4-bromo-3,5-dimethylphenyl)methanol (300 mg, 1.4 mmol) and solvated in THF (5.0 mL). The reaction was set to stir at RT under a nitrogen atmosphere and next cooled to -78 ºC. N-butyllithium (2.0N, 1.46 mL, 3.49 mmol) was added dropwise at -78 ºC. The reaction was stirred at -78 ºC for 1 h and then poured directly onto dry- ice. After 10 min. the reaction was cautiously quenched with a saturated ammonium chloride solution. The organics were removed in vacuo. The aqueous layer was next acidified to pH~2 with 1N HCl. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo to give the title compound as a pale oil (160 mg, 63%). LC/MS (Table 2, Method E) R t = 1.13 min; MS m/z: 181.0 [M+H] + . (vi) N-(2',5'-Dichloro-[1,1'-biphenyl]-3-yl)-4-(hydroxymethyl)-2, 6-dimethylbenzamide [000194] A reaction vessel was charged with 3-(2,5-dichlorophenyl)aniline (211 mg, 0.88 mmol), 4-(hydroxymethyl)-2,6-dimethylbenzoic acid (Preparation 1, 160 mg, 0.88 mmol), HATU (337 mg, 0.88 mmol) and solvated in DMF (2.0 mL). Pyridine (1.0 mL, 12.44 mmol) was added and the reaction set to stir at RT. The reaction was next allowed to warm to 80 ºC. The reaction was stirred at 80 ºC for 24 h and next cooled to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 5) to afford the title compound as a white solid (7 mg, 1.98 %). 1 H NMR (400 MHz, CD 3 OD) δ 7.76 (dd, J = 7.7, 1.0 Hz, 2H), 7.54 – 7.44 (m, 3H), 7.39 (dd, J = 8.5, 2.6 Hz, 1H), 7.24 (dd, J = 5.2, 3.9 Hz, 1H), 7.12 (s, 2H), 4.59 (s, 2H), 2.40 (s, 6H) and two exchangeable protons. LC/MS (Table 2, Method E) R t = 1.67 min; MS m/z: 399.7/410.7 [M+H] + . Example 10. Racemic 1-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrrolidine-3-carboxamide (i) Racemic ethyl 1-(2,5-dichlorophenyl)pyrrolidine-3-carboxylate [000195] A reaction vessel was charged with ethyl pyrrolidine-3-carboxylate hydrochloride (307 mg, 1.71 mmol), 2-bromo-1,4-dichlorobenzene (347 mg, 1.54 mmol), Xphos (81 mg, 0.171 mmol), tris(dibenzylideneacetone)dipalladium(0) (78 mg, 0.0854 mmol), cesium carbonate (1.76 g, 5.13 mmol) and solvated in 1,4-dioxane (11.0 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 ºC. The reaction was stirred at 80 ºC for 18 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 95 : 5, gradient elution) to afford the title compound as a yellow oil (259 mg, 58%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.20 (d, J = 8.4 Hz, 1H), 6.84 (d, J = 2.4 Hz, 1H), 6.78 (dd, J = 2.4, 8.4 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.63 (d, J = 7.4 Hz, 2H), 3.55 - 3.48 (m, 1H), 3.40 - 3.33 (m, 1H), 3.18 - 3.10 (m, 1H), 2.27 - 2.22 (m, 2H), 1.29 (dd, J = 7.1, 7.1 Hz, 3H). (ii) Racemic 1-(2,5-dichlorophenyl)pyrrolidine-3-carboxylic acid [000196] To a suspension of ethyl 1-(2,5-dichlorophenyl)pyrrolidine-3-carboxylate (256 mg, 0.888 mmol) in methanol (6.0 mL) was added lithium hydroxide monohydrate (78 mg, 1.87 mmol) in distilled water (2.0 mL). The reaction was set to stir at RT. The reaction was stirred at RT for 18 h. The organics were removed in vacuo. The aqueous layer was acidified to pH~4 with 1N HCl and the resulting precipitate filtered and dried in vacuo to afford the title compound (230 mg, quant.). ¹H NMR (400 MHz, DMSO-d 6 ) δ 12.49 (s, 2H), 7.32 (d, J = 8.5 Hz, 1H), 6.91 (d, J = 2.4 Hz, 1H), 6.86 (dd, J = 2.4, 8.4 Hz, 1H), 3.65 - 3.49 (m, 3H), 3.43 - 3.31 (m, 1H), 3.15 - 3.07 (m, 1H), 2.17 - 2.04 (m, 2H). (iii) Racemic 1-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)pyrrolidine- 3-carboxamide [000197] A reaction vessel was charged with 1-(2,5-dichlorophenyl)pyrrolidine-3- carboxylic acid (230 mg, 0.888 mmol), (4-amino-3,5-dimethylphenyl)methanol (148 mg, 0.977 mmol), HATU (507 mg, 1.33 mmol) and solvated in DMF (9.0 mL). Next, DIPEA (397 µL, 2.22 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 18 h. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 25 : 75, gradient elution). The material was further purified by reverse phase HPLC (Table 3, Method 4) to afford the title compound as a white solid (16 mg, 4.5%).¹H NMR (400 MHz, DMSO-d 6 ) δ 9.35 (s, 1H), 7.34 (d, J = 8.4 Hz, 1H), 7.02 (s, 2H), 6.95 (d, J = 2.4 Hz, 1H), 6.87 (dd, J = 2.4, 8.5 Hz, 1H), 5.12 (dd, J = 5.7, 5.7 Hz, 1H), 4.43 (d, J = 5.6 Hz, 2H), 3.66 (dd, J = 4.1, 7.5 Hz, 2H), 3.54 - 3.47 (m, 1H), 3.42 - 3.36 (m, 1H), 3.33 - 3.24 (m, 1H), 2.30 - 2.15 (m, 2H), 2.14 (s, 6H). LC/MS (Table 2, Method D) R t = 4.86 min; MS m/z: 393/395 [M+H] + . Example 11. Racemic 3-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrrolidine-1-carboxamide (i) Racemic tert-butyl 3-(2,5-dichlorophenyl)pyrrolidine-1-carboxylate [000198] A reaction vessel was charged with 2-bromo-1,4-dichlorobenzene (113 mg, 0.50 mmol), 1-boc-3-bromopyrrolidine (188 mg, 0.75 mmol), Ir[dF(CF 3 )ppy](dtbbpy)PF 6 (5.6 mg, 0.005 mmol), tris(trimethylsilyl)silane (124 mg, 0.5 mmol), 2,6-lutadine (107 mg, 1.0 mmol) and solvated in 1,2-dimethoxyethane (4.8 mL). To the reaction was added a solution of nickel pre-catalyst, itself prepared by stirring nickel (II) chloride ethylene glycol dimethyl ether complex (0.5 mg, 0.0025 mmol) and 4,4’-di-tert-butyl-2,2’-dipyridyl (0.8 mg, 0.0030 mmol) in 1,2-dimethoxyyethane (0.2 mL) under an argon atmosphere for 10 mins. The reaction was degassed and placed under an argon atmosphere. The reaction was next irradiated in an LED photoreactor for 2 h. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organic layers were washed with 10% citric acid solution, saturated sodium hydrogen carbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum ether 40-60 ºC to petroleum ether 40-60 ºC : ethyl acetate 10 : 90) to afford the title compound as a colourless oil (71 mg, 45%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.12 (d, J = 8.5 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.97 (dd, J = 2.5, 8.5 Hz, 1H), 3.69 - 3.51 (m, 2H), 3.46 - 3.37 (m, 1H), 3.30 - 3.08 (m, 3H), 2.07 (d, J = 6.0 Hz, 1H), 1.30 (s, 9H). (ii) Racemic 3-(2,5-dichlorophenyl)pyrrolidine [000199] A reaction vessel was charged with tert-butyl 3-(2,5-dichlorophenyl)pyrrolidine- 1-carboxylate (71 mg, 0.225 mmol) and solvated in DCM (1.1 mL). The reaction was set to stir at RT. Trifluoroacetic acid (1.1 mL) was added. The reaction was stirred at RT at RT for 4 h. The reaction was next concentrated in vacuo. The crude material was loaded directly onto an SCX-2 ion exchange resin and eluted with MeOH followed by 2N NH 3 in MeOH. The ammonia fraction was evaporated in vacuo to afford the title compound as a colourless oil (28 mg, 57%). ¹H NMR (400 MHz, CDCl 3 ) δ 7.28 (dd, J = 2.9, 5.5 Hz, 2H), 7.11 (dd, J = 2.5, 8.5 Hz, 1H), 3.68 - 3.59 (m, 1H), 3.37 (dd, J = 7.6, 11.0 Hz, 1H), 3.21 - 3.06 (m, 2H), 2.83 (dd, J = 7.1, 11.0 Hz, 1H), 2.30 - 2.20 (m, 1H), 1.81 (ddd, J = 7.5, 12.8, 15.3 Hz, 1H) and one exchange proton. (iii) tert-Butyl((4-isocyanato-3,5-dimethylbenzyl)oxy)dimethylsila ne [000200] A reaction vessel was charged with 4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6- dimethylaniline (Preparation 2, 80 mg, 0.301 mmol) and solvated in ethyl acetate (2.0 mL). The reaction was set to stir at RT and next phosgene (20% in toluene, 1.81 mL, 0.362 mmol) was added. The reaction was next heated at reflux for 1 h. The reaction was allowed to cool to RT and added to a solution of 2N NH 3 in MeOH (2.0 mL). The reaction was set to stir at RT and next heated at reflux for 1 h. The reaction was allowed to cool to RT and concentrated in vacuo to afford the title compound as a pale orange solid (78 mg, 89%). ¹H NMR (400 MHz, CDCl 3 ) δ 6.99 (s, 2H), 4.64 (s, 2H), 2.32 (s, 6H), 0.94 (s, 9H), 0.10 (s, 6H). (iv) Racemic 3-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)pyrrolidine- 1-carboxamide [000201] A reaction vessel was charged with 3-(2,5-dichlorophenyl)pyrrolidine (50 mg, 0.231 mmol) and solvated in toluene (0.75 mL). The reaction was set to stir at RT and tert- butyl((4-isocyanato-3,5-dimethylbenzyl)oxy)dimethylsilane (88 mg, 0.301 mmol) was added. The reaction was warmed to 110 ºC. The reaction was heated at 110 ºC for 5 h. The reaction was next allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organic layers were washed with 10% citric acid solution, saturated sodium hydrogen carbonate solution, brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 1) to afford the title compound as a white solid (29 mg, 25%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 7.58 (s, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.43 (d, J = 2.6 Hz, 1H), 7.38 (dd, J = 2.5, 8.5 Hz, 1H), 6.98 (s, 2H), 5.08 (dd, J = 5.7, 5.7 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 3.82 - 3.71 (m, 2H), 3.52 - 3.46 (m, 3H), 2.35 - 2.27 (m, 1H), 2.17 (s, 6H), 2.13 - 2.04 (m, 1H). LC/MS (Table 2, Method A) R t = 4.48 min; MS m/z: 393/395 [M+H] + . Example 12.4-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylp henyl)pyrimidine-2- carboxamide (i) Methyl 4-(2,5-dichlorophenyl)pyrimidine-2-carboxylate [000202] A reaction vessel was charged with methyl 4-bromopyrimidine-2-carboxylate (250 mg, 1.52 mmol), 2,5-dichlorophenylboronic acid (260 mg, 1.82 mmol), cesium carbonate (1120 mg, 4.56 mmol), tetrakis(triphenylphosphine)palladium(0) (130 mg, 0.152 mmol) and solvated in 1,4-dioxane (5.0 mL) and distilled water (2.0 mL). The reaction was degassed and placed under argon. The reaction was set to stir at RT and next warmed to 80 ºC. The reaction was stirred at 80 ºC 3 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : ethyl acetate, 50 : 50, gradient elution) to afford the title compound (30 mg, 9.2%). ¹H NMR (400 MHz, CDCl 3 ) δ 9.01 (d, J = 5.2 Hz, 1H), 7.90 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 2.3 Hz, 1H), 7.47 - 7.38 (m, 2H), 4.10 (s, 3H). (ii) 4-(2,5-Dichlorophenyl)pyrimidine-2-carboxylic acid [000203] To a solution of 4-(2,5-dichlorophenyl)pyrimidine-2-carboxylic acid (30 mg, 0.106 mmol) in 1,4-dioxane (3.0 mL) was added lithium hydroxide monohydrate (18 mg, 0.424 mmol) in distilled water (1.5 mL). The reaction was set to stir at RT and next warmed to 50 ºC. The reaction was heated at 50 ºC for 1 h. The reaction was allowed to cool to RT and the organics were removed in vacuo. The aqueous layer was acidified to pH~2 with 1N HCl and the resulting precipitate filtered and dried in vacuo to afford the title compound as a white solid (23 mg, 79%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 9.09 (d, J = 5.1 Hz, 1H), 8.04 (d, J = 5.2 Hz, 1H), 7.79 (s, 1H), 7.72 - 7.67 (m, 2H) and one exchangeable proton. (iii) N-(4-(((tert-Butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide [000204] A reaction vessel was charged with 4-(2,5-dichlorophenyl)pyrimidine-2- carboxylic acid (23 mg, 0.0855 mmol).4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6- dimethylaniline (Preparation 2, 25 mg, 0.094 mmol), HATU (46 mg, 0.12 mmol) and solvated in DMF (1.0 mL). DIPEA (45 µL, 0.256 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (cyclohexane to cyclohexane : diethyl ether, 50 : 50, gradient elution) to afford the title compound (40 mg, 90%). ¹H NMR (400 MHz, CDCl 3 ) δ 9.43 - 9.39 (m, 1H), 9.03 (d, J = 5.2 Hz, 1H), 7.88 (d, J = 5.1 Hz, 1H), 7.76 (d, J = 2.4 Hz, 1H), 7.47 (d, J = 8.7 Hz, 1H), 7.41 (dd, J = 2.5, 8.6 Hz, 1H), 7.07 (s, 2H), 4.68 (s, 2H), 2.31 (s, 6H), 0.94 (s, 9H), 0.10 (s, 6H). (iv) 4-(2,5-Dichlorophenyl)-N-(4-(hydroxymethyl)-2,6-dimethylphen yl)pyrimidine-2- carboxamide [000205] A reaction vessel was charged with N-(4-(((tert-butyldimethylsilyl)oxy)methyl)- 2,6-dimethylphenyl)-4-(2,5-dichlorophenyl)pyrimidine-2-carbo xamide (40 mg, 0.0774 mmol) and solvated in THF (2.0 mL). Tetrabutylammonium fluoride (1N in THF, 0.0929 mmol) was added and the reaction set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was next partitioned between ethyl acetate and sodium hydrogen carbonate. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (dichloromethane to dichloromethane : methanol, 95 : 5, gradient elution) to afford the title compound (10 mg, 30%). ¹H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.72 (d, J = 8.5 Hz, 1H), 7.67 (dd, J = 2.6, 8.6 Hz, 1H), 7.07 (s, 2H), 5.14 (dd, J = 5.7, 5.7 Hz, 1H), 4.46 (d, J = 5.7 Hz, 2H), 2.20 (s, 6H). LC/MS (Table 2, Method A) R t = 4.31 min; MS m/z: 402/404 [M+H] + . Example 13.4-(2,5-Dichlorophenyl)-N-(4-(methoxymethyl)-2,6-dimethylp henyl)pyrimidine- 2-carboxamide (i) N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5-dichloropheny l)pyrimidine-2- carboxamide [000206] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-(4-(hydroxymethyl)- 2,6-dimethylphenyl)pyrimidine-2-carboxamide (200 mg, 0.50 mmol) and solvated in CHCl 3 (10 mL). Sulfurous dichloride (180 µL, 2.5 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 2 h. The reaction was next concentrated in vacuo to give the title compound as a white solid (210 mg, 99%). LC/MS (Table 2, Method F) R t = 1.39 min; MS m/z: 419.6 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(4-(methoxymethyl)-2,6-dimethylphen yl)pyrimidine-2- carboxamide [000207] A reaction vessel was charged with N-(4-(chloromethyl)-2,6-dimethylphenyl)-4- (2,5-dichlorophenyl)pyrimidine-2-carboxamide (60 mg, 0.14 mmol) and solvated in MeOH (5 mL). Sodium methoxide (1.0M in methanol, 2.0 mL, 2.0 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (25 mg, 43%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.17 (d, J = 4.0 Hz, 1H), 8.13 (d, J = 4.0 Hz, 1H), 8.02 (d, J = 4.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.70~7.67 (m, 1H), 7.09 (s, 2H), 4.38 (s, 2H), 3.31 (s, 3H), 2.22 (s, 6H). LC/MS (Table 2, Method F) R t = 1.39 min; MS m/z: 415.7/417.6 [M+H] + . Example 14. (4-(4-(2,5-Dichlorophenyl)pyrimidine-2-carboxamido)-3,5- dimethylphenyl)methanaminium formate (i) 4-(2,5-dichlorophenyl)-N-(4-((1,3-dioxoisoindolin-2-yl)methy l)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000208] A reaction vessel was charged with N-(4-(chloromethyl)-2,6-dimethylphenyl)-4- (2,5-dichlorophenyl)pyrimidine-2-carboxamide ((Example 13, step (i), 150 mg, 0.35 mmol)) and solvated in DMF (5 mL). Potassium phthalimide (99 mg, 0.54 mmol) was added and the reaction was set to stir at RT. The reaction was next warmed to 60 ºC. The reaction was heated at 60 ºC for 5 h. The reaction was allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude product was purified by preparative TLC (petroleum spirit 40-60 ºC to petroleum spirit : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as a white solid (170 mg, 91%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.32 (s, 1H), 9.16 (d, J = 4.0 Hz, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.98~7.86 (m, 5H), 7.72 (d, J = 8.0 Hz, 1H), 7.69-7.66 (m, 1H), 7.09 (s, 2H), 4.74 (s, 2H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.39 min; MS m/z: 530.5 [M+H] + . (ii) (4-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dime thylphenyl)methanaminium formate [000209] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-(4-((1,3- dioxoisoindolin-2-yl)methyl)-2,6-dimethylphenyl)pyrimidine-2 -carboxamide (120 mg, 0.22mmol) and solvated in ethanol (5 mL). Hydrazine hydrate (98 µL, 2.5mmol) was added and the reaction was set to stir at RT. The reaction was next allowed to warm to 60°C. The reaction was heated at 60 ºC for 0.5 h. The reaction was allowed to cool to RT and concentrated in vacuo. The crude material was purified directly by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (40 mg, 45%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 9.17 (d, J = 4.0 Hz, 1H), 8.39 (brs, 1H), 8.13 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 4.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.69~7.66 (m, 1H), 7.19 (s, 2H), 4.20~3.70 (m, 2H), 3.88 (s, 2H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.07 min; MS m/z: 400.7/402.7 [M+H] + . Example 15.4-(2,5-Dichlorophenyl)-N-[3-(hydroxymethyl)-2,6-dimethylp henyl] pyrimidine- 2-carboxamide (i) (2,4-Dimethyl-3-nitrophenyl) methanol [000210] A reaction vessel was charged with 2,4-dimethyl-3-nitrobenzoic acid (300 mg, 1.23 mmol) and solvated in THF (10 mL). Borane tetrahydrofuran complex (1M, 6 mL, 6 mmol) was added at RT and the reaction was set to stir at RT. The reaction mixture was next allowed to warm to 80 ℃. The reaction was heated at 80 ºC for 1 h. The reaction was allowed to cool to RT. The reaction was quenched with distilled water and next partitioned with ethyl acetate. The organic layer was separated and the combined organic layers were washed with brine, dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 40 : 60, gradient elution) to afford the title compound as a yellow oil (250 mg, 80%). LC/MS (Table 2, Method E) R t = 1.27 min; MS m/z: 181.7 [M+H] + . (ii) (3-Amino-2,4-dimethylphenyl) methanol [000211] A reaction vessel was charged with (2,4-dimethyl-3-nitrophenyl) methanol (250 mg, 1.38 mmol), and solvated in MeOH (3 mL). The reaction was degassed and placed under argon. Palladium on carbon (100 mg) was added. The reaction was degassed and placed under a balloon of hydrogen. The reaction was set to stir at RT. The reaction was stirred at RT under an atmosphere of hydrogen for 5 h. The reaction was then degassed and placed under an atmosphere of argon. The reaction was filtered in vacuo and the filtrate concentrated in vacuo. The crude material was purified by preparative TLC (petroleum spirit 40-60 ºC to petroleum spirit : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as a yellow oil (200 mg, 90 %). LC/MS (Table 2, Method E) R t = 0.46 min; MS m/z: 152.0 [M+H] + . (iii) 4-(2,5-dichlorophenyl)-N-[3-(hydroxymethyl)-2,6-dimethylphen yl]pyrimidine-2- carboxamide [000212] A reaction vessel was charged with 4-(2,5-dichlorophenyl) pyrimidine-2- carboxylic acid ((Example 12, step (ii), 355 mg, 1.32 mmol)), (3-amino-2,4-dimethylphenyl) methanol (100 mg, 0.66 mmol), HATU (376 mg, 0.99 mmol) and solvated in DCM (4 mL). DIPEA (347 µL, 1.98 mmol) was added and the reaction was set to stir at RT. The reaction was stirred at RT for 2 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by preparative TLC (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC: ethyl acetate, 50:50, gradient elution) to afford the title compound as a white solid (50 mg, 19%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.02 (d, J = 2.5 Hz, 1H), 7.77 – 7.64 (m, 2H), 7.26 (d, J = 7.7 Hz, 1H), 7.12 (d, J = 7.7 Hz, 1H), 5.11 (s, 1H), 4.51 (s, 2H), 2.20 (s, 3H), 2.15 (s, 3H). LC/MS (Table 2, Method E) R t = 1.33 min; MS m/z: 401.6/403.6 [M+H] + . Example 16. N-(4-(2-Amino-2-oxoethoxy)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (i) 4-(2,5-Dichlorophenyl)-N-(4-hydroxy-2,6-dimethylphenyl)pyrim idine-2-carboxamide [000213] A reaction vessel was charged with 4-(2,5-dichlorophenyl)pyrimidine-2- carboxylic acid (((Example 12, step (ii), 1.0 g, 3.72 mmol)), 4-amino-3,5-dimethylphenol (0.51 g, 3.72 mmol), HATU (1.7 g, 4.46 mmol) and solvated in DMF (30 mL). DIPEA (1.3 mL, 7.44 mmol) was added. The reaction was set to stir at RT. The reaction was stirred at RT for 3 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC: ethyl acetate, 50 : 50, gradient elution) to afford the title compound as a yellow solid (1.02 g, 70.7%). LC/MS (Table 2, Method F) R t = 1.24 min; MS m/z: 387.7/389.7 [M+H] + . (ii) N-(4-(2-Amino-2-oxoethoxy)-2,6-dimethylphenyl)-4-(2,5-dichlo rophenyl)pyrimidine-2- carboxamide [000214] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-(4-hydroxy-2,6- dimethylphenyl)pyrimidine-2-carboxamide (100 mg, 0.26 mmol), cesium carbonate (169 mg, 0.52 mmol) and solvated in DMF (10 mL).2-bromoacetamide (38 mg, 0.27 mmol) was added. The reaction was set to stir at RT. The reaction was stirred at RT for 16 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by preparative TLC (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as an off-white solid (27 mg, 22.9%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.70 (dt, J = 8.6, 5.6 Hz, 2H), 7.51 (s, 1H), 7.40 (s, 1H), 6.75 (s, 2H), 4.42 (s, 2H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.21 min; MS m/z: 444.6/446.6 [M+H] + . Example 17.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2-(methylamino) -2- oxoethoxy)phenyl)pyrimidine-2-carboxamide (i) Ethyl 2-(4-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)-3,5- dimethylphenoxy)acetate [000215] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-(4-hydroxy-2,6- dimethylphenyl)pyrimidine-2-carboxamide ((Example 16, step (i), 268 mg, 0.69 mmol)), cesium carbonate (450 mg, 1.38 mmol) and solvated in DMF (15 mL). Ethyl 2-bromoacetate (127 mg, 0.76 mmol) was added. The reaction was set to stir at RT. The reaction was stirred at RT for 16 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as an off-white solid. LC/MS (Table 2, Method F) R t = 1.39 min; MS m/z: 473.6/475.6 [M+H] + . (i) 4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2-(methylamino)-2- oxoethoxy)phenyl)pyrimidine- 2-carboxamide [000216] A reaction vessel was charged with ethyl 2-(4-(4-(2,5- dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylphenoxy )acetate (100 mg, 0.21 mmol) and solvated in MeOH (5 mL). The reaction was set to stir at RT under a nitrogen atmosphere. Methylamine (33% wt in methanol, 12 mL, 127.5 mmol) was added. The reaction was stirred at RT for 16 h. The reaction was next concentrated in vacuo. This crude material was purified directly by preparative TLC (neat ethyl acetate) to afford the title compound as a white solid (46 mg, 47.3%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.21 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.01 (dd, J = 7.5, 3.5 Hz, 2H), 7.70 (dt, J = 8.6, 5.6 Hz, 2H), 6.77 (s, 2H), 4.46 (s, 2H), 2.67 (d, J = 4.7 Hz, 3H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.26 min; MS m/z: 458.6/460.6 [M+H] + . Example 18.4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxyethoxy)-2,6-dimethy lphenyl)pyrimidine- 2-carboxamide (i) Ethyl 2-(4-amino-3,5-dimethylphenoxy)acetate [000217] A reaction vessel was charged with 4-amino-3,5-dimethylphenol (1.0 g, 7.3 mmol) and solvated in acetonitrile (50 mL). Ethyl 2-bromoacetate (1.28 g, 7.6 mmol) and cesium carbonate (5.19 g, 15.9 mmol) were added. The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 16 h. The reaction was next filtered and concentrated in vacuo. The crude material was purified directly by flash column chromatography eluting (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as a red solid (1.2 g, 73.97%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.46 (s, 2H), 4.56 (s, 2H), 4.15 (d, J = 7.1 Hz, 4H), 2.05 (s, 6H), 1.21 (t, J = 7.1 Hz, 3H). LC/MS (Table 2, Method F) R t = 0.99 min; MS m/z: 224.0 [M+H] + . (ii) 2-(4-Amino-3,5-dimethylphenoxy)ethan-1-ol [000218] A reaction vessel was charged with ethyl 2-(4-amino-3,5- dimethylphenoxy)acetate (200 mg, 0.9 mmol) and solvated in THF (10 mL). The reaction was set to stir at RT under a nitrogen atmosphere and next cooled to 0 ºC. Lithium aluminium hydride (1.0 M in THF, 1.89 mL, 1.89 mmol) was added at 0 ºC. The reaction was allowed to warm to RT and stirred at RT for 16 h. The reaction was next cooled to 0 ºC and quenched with MeOH (1 mL) and 10% aqueous NaOH solution (1 mL). The organics were removed in vacuo. The aqueous layer was acidified to pH~6-7 with 1N hydrochloric acid solution. The reaction was partitioned with ethyl acetate. The organic layer was separated and the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC (neat ethyl acetate) to afford the title compound as an orange solid (83 mg, 51%) as an orange solid. LC/MS (Table 2, Method F) R t = 0.32 min; MS m/z: 182.0 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxyethoxy)-2,6-dimethylph enyl)pyrimidine-2- carboxamide [000219] A reaction vessel was charged with 4-(2,5-dichlorophenyl)pyrimidine-2- carboxylic acid ((Example 12, step (ii), 124 mg, 0.46 mmol)), 2-(4-amino-3,5- dimethylphenoxy)ethanol (83 mg, 0.46 mmol), HATU (210 mg, 0.55 mmol) and solvated in DMF (10 mL). DIPEA (161 µL, 0.92 mmol) was added. The reaction was set to stir at RT. The reaction was stirred at RT for 16 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 40 : 60, gradient elution) to afford the title compound as a white solid (33.6 mg, 16.89%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.18 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.70 (dt, J = 8.6, 5.5 Hz, 2H), 6.73 (s, 2H), 4.87 (t, J = 5.5 Hz, 1H), 3.98 (t, J = 5.1 Hz, 2H), 3.72 (dd, J = 10.2, 5.1 Hz, 2H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.27 min; MS m/z: 431.7/433.7 [M+H] + . Example 19.4-(2,5-Dichlorophenyl)-N-(4-(2-(dimethylamino)-2-oxoethox y)-2,6- dimethylphenyl)pyrimidine-2-carboxamide (i) 2-(4-(4-(2,5-Dichlorophenyl)pyrimidine-2-carboxamido)-3,5-di methylphenoxy)acetic acid [000220] A reaction vessel was charged with ethyl 2-(4-(4-(2,5- dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylphenoxy )acetate ((Example 17, step (i) 189 mg, 0.4 mmol)) and solvated in MeOH (5 mL) and distilled water (10 mL). Sodium hydroxide (800 mg, 20 mmol) was added. The reaction was set to stir at RT and next heated at 50 ℃ for 2 h. The reaction was allowed to cool to RT. The organics were removed in vacuo. The aqueous layer was acidified to pH ~6-7 with with 1N hydrochloric acid and partitioned with ethyl acetate. The organic layer was separated and the combined organic layers were dried (MgSO 4 ) and concentrated in vacuo to give the title compound as a yellow solid (162 mg, 88.5%). LC/MS (Table 2, Method F) R t = 1.27 min; MS m/z: 445.6/447.6 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(4-(2-(dimethylamino)-2-oxoethoxy)- 2,6- dimethylphenyl)pyrimidine-2-carboxamide [000221] A reaction vessel was charged with 4-[4-(2,5-dichlorophenyl)pyrimidine-2- amido]-3,5-dimethylphenoxyacetic acid (162 mg, 0.36 mmol), HATU (166 mg, 0.432 mmol) and solvated in DMF (10 mL). Dimethylamine (2M in THF, 0.2 mL, 0.36 mmol) and DIPEA (126 µL, 0.72 mmol) were added. The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 16 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (53.4 mg, 31.3%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.19 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.70 (dt, J = 8.6, 5.6 Hz, 2H), 6.72 (s, 2H), 4.79 (s, 2H), 3.02 (s, 3H), 2.86 (s, 3H), 2.17 (s, 6H). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 472.6/474.6 [M+H] + . Example 20. N-(4-(Acetamidomethyl)-2,6-dimethylphenyl)-4-(2,5-dichloroph enyl)pyrimidine- 2-carboxamide (i) N-[4-(Aminomethyl)-2,6-dimethylphenyl]-4-(2,5-dichlorophenyl )pyrimidine-2-carboxamide [000222] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-{4-[(1,3-dioxoisoindol- 2-yl)methyl]-2,6-dimethylphenyl}pyrimidine-2-carboxamide ((Example 14, step (i), 150 mg, 0.28 mmol)) and solvated in ethanol (5 mL). Hydrazine hydrate (560 µL, 2.8 mmol) was added. The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was next warmed to reflux. The reaction was heated at reflux for 4 h. The reaction was allowed to cool to RT. The reaction was filtered and the filtrate was concentrated in vacuo. The residue was purified by preparative TLC (DCM to DCM : MeOH, 80 : 20, gradient elution) to afford the title compound (100 mg, 89% yield) as a white solid. LC/MS (Table 2, Method E) R t = 1.13 min; MS m/z: 400.7/402.7 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-[4-(acetamidomethyl)-2,6-dimethylph enyl]pyrimidine-2- carboxamide [000223] To a solution of N-[4-(aminomethyl)-2,6-dimethylphenyl]-4-(2,5-dichlorophenyl )pyrimidine- 2-carboxamide (50 mg, 0.12 mmol) in DCM (3 mL) was added acetic anhydride (15 mg, 0.14 mmol). The reaction was set to stir at RT under an atmosphere of nitrogen. The reaction was stirred at RT for 2 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (28 mg, Purity 98.9%). 1 H NMR (400 MHz, CD 3 OD) δ 9.12 (d, J = 5.0 Hz, 1H), 8.11 (d, J = 5.0 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.59 (dt, J = 8.6, 5.6 Hz, 2H), 7.11 (s, 2H), 4.34 (s, 2H), 2.30 (s, 6H), 2.02 (s, 3H) and two exchangeable protons. LC/MS (Table 2, Method E) R t = 1.31 min; MS m/z: 442.6/444.6 [M+H] + . Example 21. N-(4-Cyano-2,6-dimethylphenyl)-4-(2,5-dichlorophenyl)pyrimid ine-2- carboxamide (i) 4-(2,5-Dichlorophenyl)pyrimidine-2-carbonyl chloride [000224] A reaction vessel was charged with 4-(2,5-dichlorophenyl)pyrimidine-2- carboxylic acid ((Example 12, step (ii), 386 mg, 1.43 mmol)) and solvated in DCM (10 mL). The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was cooled to 0 ºC and oxalyl chloride (0.16 mL, 1.86 mmol) and cat. DMF (1-2 drops) were added. The reaction was allowed to warm to RT and stirred at RT for 1 h. The reaction was next concentrated in vacuo to afford 4-(2,5-dichlorophenyl)pyrimidine-2-carbonyl chloride as a yellow solid (412 mg, 1.44 mmol, quant.) which was used directly in the next reaction. (ii) N-(4-Cyano-2,6-dimethylphenyl)-4-(2,5-dichlorophenyl)pyrimid ine-2-carboxamide [000225] 4-(2,5-dichlorophenyl)pyrimidine-2-carbonyl chloride (412 mg, 1.44 mmol) was dissolved in toluene (15 mL) and set to stir at RT under an atmosphere of nitrogen.4-Amino- 3,5-dimethylbenzonitrile (271.76 mg, 1.86 mmol) and triethylamine (0.56 mL, 404 mmol) were added. The reaction was stirred at RT and next allowed to warm to 110 ℃. The reaction was heated at 110 ºC for 24 h. The reaction was allowed to cool to RT. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by preparative TLC (DCM to DCM : ethyl acetate, 97 : 3, gradient elution) to give the title product as a white solid (101.9 mg, 18% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.62 (s, 1H), 9.18 (d, J = 4 Hz, 1H), 8.14 (d, J = 4 Hz, 1H), 7.98 (d, J = 4 Hz, 1H), 7.75~7.67 (m, 4H), 2.27 (s, 6H). LC/MS (Table 2, Method F) R t = 1.36 min; MS m/z: 396.6/398.6 [M+H] + . Example 22.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4- (methylsulfonamidomethyl)phenyl)pyrimidine-2-carboxamide [000226] A reaction vessel was charged with N-[4-(aminomethyl)-2,6-dimethylphenyl]-4- (2,5-dichlorophenyl)pyrimidine ((Example 20, step (i), 80 mg, 0.2 mmol)) and solvated in DCM (2 mL). The reaction was set to stir at RT and next cooled to 0 ºC. Methanesulfonyl chloride (16 µL, 0.2 mmol) and triethylamine (42 µL, 0.3 mmol) were added at 0℃. The reaction was allowed to warm to RT and stirred at RT for 1.5 h. The reaction was next partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (46.9 mg, 49% yield). 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.70 (dt, J = 8.6, 5.6 Hz, 2H), 7.54 (t, J = 6.3 Hz, 1H), 7.12 (s, 2H), 4.12 (d, J = 6.2 Hz, 2H), 2.91 (s, 3H), 2.22 (s, 6H). LC/MS (Table 2, Method E) R t = 1.36 min; MS m/z: 478.6/480.6 [M+H] + . Example 23.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide (i) Ethyl 4-[4-(2,5-dichlorophenyl)pyrimidine-2-amido]-3,5-dimethylben zoate [000227] A reaction vessel was charged with 4-(2,5-dichlorophenyl)pyrimidine-2- carbonyl chloride (247 mg, 0.86 mmol) in toluene (3 mL). Ethyl 4-amino-3,5- dimethylbenzoate (150 mg, 0.78 mmol) and DIPEA (409 µL, 2.34 mmol). The reaction was set to stir at RT under an atmosphere of nitrogen. The reaction was next warmed to 100 ℃. The reaction was heated at 100 ºC for 16 h. The reaction was next allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by preparative TLC (DCM to DCM : methanol, 95 : 5, gradient elution) to afford the title compound as a light yellow solid (200 mg, 54.8%). LC/MS (Table 2, Method F) R t = 1.43 min; MS m/z: 443.6 [M+H] + . (ii) 4-[4-(2,5-Dichlorophenyl)pyrimidine-2-amido]-3,5-dimethylben zoic acid [000228] To a solution of ethyl 4-[4-(2,5-dichlorophenyl)pyrimidine-2-amido]-3,5- dimethylbenzoate (200 mg, 0.4 mmol) in MeOH (3 mL) and distilled water (1 mL) was added sodium hydroxide (120 mg, 3.6 mmol). The reaction was set to stir at RT. The reaction was stirred at RT for 16 h. The organics were removed in vacuo. The aqueous layer was acidified to pH~5 with 1N hydrochloric acid solution. The reaction was next partitioned with ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo to afford the title compound (150 mg, 88.3%). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 415.6 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-[2,6-dimethyl-4-(methylcarbamoyl)ph enyl]pyrimidine-2- carboxamide [000229] A reaction vessel was charged with 4-[4-(2,5-dichlorophenyl)pyrimidine-2- amido]-3,5-dimethylbenzoic acid (150 mg, 0.31 mmol), HATU (176.8 mg, 0.46 mmol) and solvated in DMF (3 mL). Methylamine hydrochloride (31.3.7 mg, 0.46 mmol) and DIPEA (162 µL, 0.93 mmol) were added. The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 3 h. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO4) and concentrated in vacuo. The crude material was purified by preparative TLC (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 50 : 50, gradient elution) to afford the title compound as a white solid (80 mg, 57.4%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.47 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.40 (m, 1H), 8.13 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.70 (dt, J = 8.6, 5.6 Hz, 2H), 7.61 (s, 2H), 2.77 (t, J = 11.6 Hz, 3H), 2.26 (s, 6H). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 428.7/430.7 [M+H] + . Example 24. N-(3-(Aminomethyl)-2,6-dimethylphenyl)-4-(2,5-dichlorophenyl )pyrimidine-2- carboxamide (i) N-[3-(Chloromethyl)-2,6-dimethylphenyl]-4-(2,5-dichloropheny l)pyrimidine-2-carboxamide [000230] A reaction vessel was charged with 4-(2,5-dichlorophenyl)-N-[3- (hydroxymethyl)-2,6-dimethylphenyl]pyrimidine (Example 15, 30 mg, 0.1 mmol) and solvated in CHCl 3 (4.0 mL). Cat. DMF (0.05 mL, 0.65 mmol) and thionyl chloride (7.5 µL, 0.1 mmol) were added. The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 0.5 h and next concentrated in vacuo to afford the title compound as a yellow solid (30 mg, 90 %). LC/MS (Table 2, Method E) Rt = 1.56 min; MS m/z: 419.6/421.6 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-{3-[(1,3-dioxoisoindol-2-yl)methyl] -2,6-dimethylphenyl} pyrimidine-2- carboxamide [000231] A reaction vessel was charged with N-[3-(chloromethyl)-2,6-dimethylphenyl]-4- (2,5-dichlorophenyl) pyrimidine (30 mg, 0.1 mmol) and DMF (3.0 mL).2H-indene-1,3-dione (22 mg, 0.15 mmol) was added and the reaction was set to stir at RT under nitrogen atmosphere. The reaction was next warmed to 60 ºC. The reaction was heated at 60 ºC for 2 h. The reaction was allowed to cool to RT and concentrated in vacuo. The crude material was purified directly by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 10 : 90, gradient elution) to afford the title compound as a white solid (21 mg, 39% yield). LC/MS (Table 2, Method E) R t = 1.56 min; MS m/z: 530.5/532.5 [M+H] + . (iii) N-[3-(Aminomethyl)-2,6-dimethylphenyl]-4-(2,5-dichlorophenyl ) pyrimidine-2-carboxamide [000232] To a solution of 4-(2,5-dichlorophenyl)-N-{3-[(1,3-dioxoisoindol-2-yl) methyl]- 2,6-dimethylphenyl} pyrimidine-2-carboxamide (30 mg, 0.056 mmol) in EtOH (5 mL) was added hydrazine hydrate (28 mg, 0.56 mmol). The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was next warmed to 60 ºC. The reaction was heated at 60 ºC for 4 h. The reaction was allowed to cool to RT. The reaction was filtered and the filtrate concentrated in vacuo. The crude material was purified was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (15.4 mg, 68% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.38 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.70 (dt, J = 8.6, 5.6 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 5.77 (s, 2H), 3.90 (s, 2H), 2.20 (d, J = 6.7 Hz, 6H). LC/MS (Table 2, Method E) R t = 1.15 min; MS m/z: 400.7/402.7 [M+H] + . Example 25. N-(4-(4-(2,5-Dichlorophenyl)pyrimidine-2-carboxamido)-3,5-di methylbenzyl)- 2-fluoroethan-1-aminium formate [000233] To a solution of N-[4-(chloromethyl)-2,6-dimethylphenyl]-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide ((Example 13, step (i), 130 mg, 0.31 mmol)) in DMF (4 mL) was added 2-fluoroethanamine (55 µL, 0.775 mmol), K 2 CO 3 (215 mg, 1.55 mmol) and KI (3 mg, 0.018 mmol). The reaction was set to stir at RT under a nitrogen atmosphere. The reaction was next warmed to reflux. The reaction was heated at reflux for 4 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as white solid (22.9 mg, 15% yield). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.19 (s, 1H), 8.12 (d, J = 5.2, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 8.6, 2.5 Hz, 1H), 7.10 (s, 2H), 4.52 (dt, J = 50, 5.1 Hz, 2H), 3.74 (s, 2H), 2.84 (dt, J = 28, 5.1 Hz, 2H), 2.21 (s, 6H) and one exchangeable proton. LC/MS (Table 2, Method E) R t = 1.18 min; MS m/z: 446.6/448.7 [M+H] + . Example 26.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2-oxopyrrolidin -1- yl)phenyl)pyrimidine-2-carboxamide [000234] A reaction vessel was charged with 4-(2,5-dichlorophenyl)pyrimidine-2- carboxylic acid ((Example 12, step (ii), 86 mg, 0.32 mmol), 1-(4-amino-3,5- dimethylphenyl)pyrrolidin-2-one (CAS924830-53-5, 64.5 mg, 0.32 mmol), HATU (146 mg, 0.38 mmol) and solvated in DMF (6 mL). DIPEA (0.11 mL, 0.786 mmol) was added and the reaction set to stir at RT under an atmosphere of nitrogen. The reaction was stirred at RT for 2 h. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC Table 3, Method 6) to afford the title compound as a white solid (43.8 mg,0.097 mmol). 1 H NMR (400 MHz, CD3OD) δ 9.12 (d, J = 4 Hz, 1H), 8.10 (d, J = 4 Hz, 1H), 7.97 (d, J = 4 Hz, 1H), 7.63 (d, J = 8 Hz, 1H), 7.59-7.56 (m, 1H), 7.44 (s, 2H), 3.96 (t, J = 8 Hz, 2H), 2.62 (t, J = 8 Hz, 2H), 2.33 (s, 6H), 2.20 (m, 2H) and one exchangeable proton. LC/MS (Table 2, Method F) R t = 1.27 min; MS m/z: 454.7/456.7 [M+H] + . Example 27.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-3- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide (i) N,2,4-Trimethyl-3-nitrobenzamide [000235] A reaction vessel was charged with 2,4-dimethyl-3-nitrobenzoic acid (200 mg, 0.02 mmol), HATU (581 mg, 1.53 mmol) and solvated in DMF (3.0 mL). DIPEA (534 µL, 3.06 mmol) was added and the reaction was set to stir at RT under a nitrogen atmosphere. The reaction was stirred at RT for 2 h. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 65 : 35, gradient elution) to afford the title compound as a white solid (150 mg, 36% yield). LC/MS (Table 2, Method E) R t = 1.15 min; MS m/z: 208.9 [M+H] + . (ii) 3-Amino-N,2,4-trimethylbenzamide [000236] A reaction vessel was charged with N,2,4-trimethyl-3-nitrobenzamide (250 mg, 1.38 mmol) and solvated in MeOH (3.0 mL). The reaction was degassed and placed under argon. Pd/C (100 mg) was added and the reaction was degassed and placed under a hydrogen atmosphere. The reaction was stirred at RT for 5 h. The reaction was next filtered under argon and the filtrate concentrated in vacuo. The crude material was purified by flash column chromatography (petroleum spirit 40-60 ºC to petroleum spirit 40-60 ºC : ethyl acetate, 35 : 65, gradient elution) to afford the title compound as a white solid (150 mg, 42% yield). LC/MS (Table 2, Method E) R t = 0.63 min; MS m/z: 179.0 [M+H] + . (iii) 3-(((4-(2,5-Dichlorophenyl) pyrimidin-2-yl) methyl) amino)-N,2,4-trimethylbenzamide [000237] A reaction vessel was charged with 4-(2,5-dichlorophenyl) pyrimidine-2- carbonyl chloride ((Example 21, step (i), 100 mg, 0.35 mmol)), 3-amino-N,2,4- trimethylbenzamide (68 mg, 0.38 mmol) and solvated in toluene (5.0 mL). DIPEA (174 µL, 1 mmol) was added and the reaction set to stir at RT under an atmosphere of nitrogen. The reaction was next allowed to warm to 110 ºC and stirred at 110 ℃ for 24 h. The reaction was allowed to cool to RT. The reaction was partitioned between ethyl acetate and distilled water. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude material was purified by reverse phase HPLC (Table 3, Method 6) to afford the title compound as a white solid (25 mg, 16% yield). 1 H NMR (400 MHz, CD 3 OD) δ 9.13 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 2.5 Hz, 1H), 7.61 (dd, J = 18.5, 5.6 Hz, 2H), 7.27 (d, J = 8.9 Hz, 2H), 2.92 (s, 3H), 2.34 (d, J = 3.1 Hz, 6H) and two exchangeable protons. LC/MS (Table 2, Method E) R t = 1.33 min; MS m/z: 428.6/430.6 [M+H] + . Preparation Preparation 1. (4-Amino-3,5-dimethylphenyl)methanol [000238] A reaction vessel was charged with (3,5-dimethyl-4-nitrophenyl)methanol (1.0 g, 5.52 mmol), ammonium chloride (1.48 g, 27.6 mmol) and solvated in EtOH (30 mL) and distilled water (10 mL). Iron powder (0.92 g, 16.56 mmol) was added and the reaction was set to stir at RT. The reaction was next warmed to reflux and heated at reflux for 45 minutes. The reaction was allowed to cool to RT and filtered in vacuo. The filtrate was concentrated in vacuo and the crude material was purified by flash column chromatography (cyclohexane to ethyl acetate gradient elution) to afford the title compound (484 mg, 58%) as an off white solid. ¹H NMR (400 MHz, CDCl 3 ) δ 6.96 (s, 2H), 4.52 (s, 2H), 3.64 (br s, 2H), 2.19 (s, 6H) and one exchangeable proton. Preparation 2.4-(((Tert-Butyldimethylsilyl)oxy)methyl)-2,6-dimethylanili ne [000239] A reaction vessel was charged with 4-amino-3,5-dimethylphenyl)methanol (60 mg, 0.397 mmol) and solvated in DCM (2.0 mL). Tert-butyldimethylsilyl chloride (72 mg, 0,476 mmol), triethylamine (100 µL, 0.794 mmol) and 4-dimethylaminopyridine (4.8 mg, 0.0397 mmol) were added and the reaction was set to stir at RT. The reaction was stirred at RT for 1 h. The reaction was next partitioned between ethyl acetate and sodium hydrogen carbonate. The organic layer was separated and the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The crude residue was purified by flash column chromatography (DCM to DCM : MeOH, 98 : 2, gradient elution) to afford the title compound (66 mg, 40%) as a clear oil. ¹H NMR (400 MHz, CDCl 3 ) δ 6.91 (s, 2H), 4.60 (s, 2H), 3.52 (s, 2H), 2.18 (s, 6H), 0.95 (s, 9H), 0.10 (s, 6H). Example 28.4-(2,5-Dichlorophenyl)-N-(4-(dimethylcarbamoyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000240] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(4-(2,5- dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylbenzoic acid and 2M dimethylamine in THF. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.44 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.73 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 8.6, 2.5 Hz, 1H), 7.18 (s, 2H), 2.99 (s, 3H), 2.96 (s, 3H), (s, 6H), 2.24 (s, 6H). LC/MS (Table 2, Method E) R t = 1.34 min; MS m/z: 443/445 [M+H] + . Example 29.4-(2,5-Dichlorophenyl)-N-(5-(hydroxymethyl)-2,4-dimethylp henyl)pyrimidine-2- carboxamide [000241] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and (5-amino-2,4-dimethylphenyl)methanol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.5 Hz, 1H), 7.67 (s, 1H), 7.06 (s, 1H), 5.11 (t, J = 5.4 Hz, 1H), 4.48 (d, J = 5.4 Hz, 2H), 2.24 (s, 3H), 2.22 (s, 3H). LC/MS (Table 2, Method F) R t = 1.46 min; MS m/z: 402/404 [M+H] + . Example 30. N-(4-(Hydroxymethyl)-2,6-dimethylphenyl)-4-phenylpyrimidine- 2-carboxamide (i) Ethyl 4-methoxypyrimidine-2-carboxylate [000242] A mixture of 2-chloro-4-methoxypyrimidine (1.44 g, 10.0 mmol), Pd(dppf)Cl 2 (365.5 mg, 0.5 mmol), EtOH (30 mL) and triethylamine (1.38 mL, 20.0 mmol) in a steel pressure vessel was purged with nitrogen, degassed and pressurized with carbon monoxide to 1.0 MPa. The resulting mixture was heated at 100ºC for 15 h. The mixture was cooled to RT, evacuated, filled with nitrogen and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a yellow oil (910 mg, 50% yield). 1 H NMR (400 MHz, CDCl 3 ) δ 8.59 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 4.52 (q, J = 8.0 Hz, 2H), 4.11 (s, 3H), 1.47 (t, J = 8.0 Hz, 3H). (ii) Ethyl 4-hydroxypyrimidine-2-carboxylate [000243] A solution of ethyl 4-methoxypyrimidine-2-carboxylate (770 mg, 4.21 mmol) in acetonitrile (20 mL) was treated with sodium iodide (3.15 g, 21.0 mmol) and trimethylsilyl chloride (2.28 g, 21.0 mmol), and the resulting mixture was stirred at 60ºC for 16 h. The mixture was cooled to RT and partitioned between EtOAc and saturated aqueous sodium sulphite solution. The organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the title compound as a white solid (350 mg, 49%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.92 (s, 1H), 8.15 (s, 1H), 6.69 (s, 1H), 4.32 (q, J = 8.0 Hz, 2H), 1.32 (t, J = 8.0 Hz, 3H). (iii) 4-Hydroxypyrimidine-2-carboxylic acid [000244] A mixture of ethyl 4-hydroxypyrimidine-2-carboxylate (52 mg, 0.31 mmol) and MeOH (2 mL) was treated with lithium hydroxide monohydrate (3M LiOH solution, 1 mL, 3 mmol), and the resulting mixture was stirred at RT for 3 h. The mixture was concentrated in vacuo and the reside adjusted to pH ~3 with 1N HCl. The resulting precipitate was collected by filtration to afford the title compound as a white solid (35 mg, 83%). LC/MS (Table 1, Method F) R t = 0.19 min; MS m/z: 139 [M-H] + . (iv) 4-Chloropyrimidine-2-carbonyl chloride [000245] A solution of 4-hydroxypyrimidine-2-carboxylic acid (40 mg, 0.29 mmol) in CHCl 3 (5 mL) was treated with sulfurous dichloride (178.5 mg, 1.5 mmol) and DMF (0.1-0.2 mL), and the resulting mixture was heated at reflux for 16 h. The mixture was cooled to RT and concentrated in vacuo to afford the title compound (49.5 mg, 99%) which was used directly in the next reaction. LC/MS (Table 1, Method F) R t = 0.90 min; MS m/z: 173/175 [M+H] + (methyl ester). (v) 4-Chloro-N-(4-(hydroxymethyl)-2,6-dimethylphenyl)pyrimidine- 2-carboxamide [000246] The title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(2,6-dimethyl-3-(methylcarbamoyl)ph enyl)pyrimidine- 2-carboxamide from the appropriate starting materials (4-chloropyrimidine-2-carbonyl chloride and 4-amino-3,5-dimethylphenyl)methanol (CAS: 89210-26-4)). LC/MS (Table 1, Method F) R t = 1.07 min; MS m/z: 293/295[M+H] + . (vi) N-(4-(Hydroxymethyl)-2,6-dimethylphenyl)-4-phenylpyrimidine- 2-carboxamide [000247] A mixture of 4-chloro-N-(4-(hydroxymethyl)-2,6-dimethylphenyl)pyrimidine- 2- carboxamide (291 mg, 1.0 mmol), phenylboronic acid (CAS: 98-80-6, 183 mg, 1.5 mmol), Pd(dppf)Cl 2 (73.1 mg, 0.1 mmol), potassium carbonate (41.4 mg, 3.0 mmol), 1,4-dioxane (10 mL) and distilled water (2 mL) was degassed and placed under an atmosphere of argon before being heated at 90ºC for 24 h. The mixture was cooled to RT, partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC (EtOAc) to afford the title compound as an off-white solid (35 mg, 11%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.07 (d, J = 4.0 Hz, 1H), 8.46 - 8.44 (m, 2H), 8.31 (d, J = 4.0 Hz, 1H), 7.62 - 7.59 (m, 3H), 7.09 (s, 2H), 5.17 (t, J = 4.0 Hz, 1H), 4.48 (d, J = 4.0 Hz, 2H), 2.22 (s, 6H). LC/MS (Table 2, Method F) R t = 1.18 min; MS m/z: 334 [M+H] + . [000248] The following Examples in Table 4 were prepared using an analogous method to N-(4-(hydroxymethyl)-2,6-dimethylphenyl)-4-phenylpyrimidine- 2-carboxamide using 4- chloro-N-(4-(hydroxymethyl)-2,6-dimethylphenyl)pyrimidine-2- carboxamide and a suitable boronic acid or boronate. Table 4.
Example 31.4-(5-Chloro-2-methylphenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000249] 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 9.08 (s, 1H), 7.65 (s, 1H), 7.55 (d, J = 1.6 Hz, 1H), 7.41 (dd, J = 8.0, 1.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.17 (s, 2H), 4.68 (s, 2H), 2.49 (s, 3H), 2.35 (s, 6H). LC/MS (Table 2, Method E) R t = 1.46 min; MS m/z: 382 [M+H] + . Example 32.4-(2,5-Dimethylphenyl)-N-(4-(hydroxymethyl)-2,6-dimethylp henyl)pyrimidine-2- carboxamide [000250] 1 H NMR (400 MHz, CDCl 3 ) δ 9.48 (s, 1H), 9.04 (d, J = 3.2 Hz, 1H), 7.65 (d, J = 3.2 Hz, 1H), 7.38 (s, 1H), 7.24 (s, 2H), 7.16 (s, 2H), 4.67 (s, 2H), 2.49 (s, 3H), 2.43 (s, 3H), 2.35 (s, 6H). LC/MS (Table 2, Method E) R t = 1.45 min; MS m/z: 362 [M+H] + . Example 33.4-(2-Chloro-5-cyanophenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000251] 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 9.10 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 5.2 Hz, 1H), 7.77 (dd, J = 8.0, 2.0 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.18 (s, 2H), 4.68 (s, 2H), 2.36 (s, 6H). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 393 [M+H] + . Example 34.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2- (methylamino)ethoxy)phenyl)pyrimidine-2-carboxamide formic acid salt [000252] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(2-Amino-2-oxoethoxy)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)-N-(4-hydroxy-2,6-dimethylphenyl)pyrimidine-2 -carboxamide and tert-butyl (2-chloroethyl)(methyl)carbamate (CAS: 220074-38-4)). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.20 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.30 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.69 (dd, J = 8.4, 2.4 Hz, 1H), 6.75 (s, 2H), 4.10 (t, J = 5.2 Hz, 2H), 3.02 (t, J = 5.2 Hz, 2H), 2.46 (s, 3H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.12 min; MS m/z: 445/447 [M+H] + . Example 35.4-(2,5-Dichlorophenyl)-N-(3-(2-hydroxyethoxy)-2,6-dimethy lphenyl)pyrimidine- 2-carboxamide (i) Ethyl 2-(3-amino-2,4-dimethylphenoxy)acetate [000253] A solution of 3-amino-2,4-dimethylphenol (CAS: 100445-96-3, 3 g, 21.9 mmol) in MeCN (100 mL) at 0℃ was treated with ethyl 2-bromoacetate (CAS: 105-36-2, 2.6 mL, 22.9 mmol) and Cs 2 CO 3 (15.6 g, 47.7 mmol), and the resulting mixture was stirred at RT for 16 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40- 60ºC:EtOAc, gradient elution) to afford the title compound as a yellow oil (4.4 g, 89 %). 1 H NMR (400 MHz, DMSO-d 6 ) δ 6.69 (d, J = 8.1 Hz, 1H), 6.01 (d, J = 8.1 Hz, 1H), 4.61 (s, 2H), 4.55 (s, 2H), 4.20 (q, J = 7.2 Hz, 2H), 1.99 (s, 3H), 1.97 (s, 3H), 1.19 (t, J = 6.9 Hz, 3H). LC/MS (Table 2, Method F) R t = 1.19 min; MS m/z: 224 [M+H] + . (ii) 2-(3-Amino-2,4-dimethylphenoxy)ethan-1-ol [000254] A solution of ethyl 2-(3-amino-2,4-dimethylphenoxy)acetate (2 g, 9 mmol) in THF (100 mL) at 0ºC was treated with LiAlH 4 (0.72 g, 18.9 mmol) and the resulting mixture was stirred at RT for 16 h. The mixture was cooled to 0ºC, diluted with MeOH and a 10% aqueous sodium hydroxide solution. The mixture was filtered and the filtrate adjusted to pH 6-7 with 2N HCl before being extracted with ethyl acetate. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a yellow oil (1.2 g, 72% yield). LC/MS (Table 2, Method F) R t = 0.87 min; MS m/z: 182 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(3-(2-hydroxyethoxy)-2,6-dimethylph enyl)pyrimidine-2- carboxamide [000255] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and 2-(3-amino-2,4-dimethylphenoxy)ethan-1- ol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.34 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.68 (dd, J = 8.8, 2.8 Hz, 1H), 7.07 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.86 (t, J = 5.2 Hz, 1H), 3.99 (t, J = 4.8 Hz, 2H), 3.74 (q, J = 4.8 Hz, 2H), 2.15 (s, 3H), 2.08 (s, 3H). LC/MS (Table 2, Method F) R t = 1.29 min; MS m/z: 432/434 [M+H] + . Example 36.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-3-(2- (methylamino)ethoxy)phenyl)pyrimidine-2-carboxamide (i) 4-(2,5-Dichlorophenyl)-N-(3-hydroxy-2,6-dimethylphenyl)pyrim idine-2-carboxamide [000256] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and 3-amino-2,4-dimethylphenol (CAS: 100445-96-3)). LC/MS (Table 2, Method F) R t = 1.24 min; MS m/z: 388/390 [M+H] + . (ii) tert-Butyl (2-(3-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)-2,4- dimethylphenoxy)ethyl)(methyl)carbamate [000257] A mixture of 4-(2,5-dichlorophenyl)-N-(3-hydroxy-2,6- dimethylphenyl)pyrimidine-2-carboxamide (250 mg, 0.64 mmol), tert-butyl (2- chloroethyl)(methyl)carbamate (CAS: 220074-38-4, 249 mg, 1.28 mmol), potassium iodide (106 mg, 0.64 mmol), potassium hydroxide (108 mg, 1.92 mmol) and DMF (5 mL) was heated under microwave irradiation at 100 ℃ for 1 h. The mixture was cooled to RT, partitioned between EtOAc and distilled water, and the organic layer dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC (petroleum spirit 40- 60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a white solid (100 mg, 29%). LC/MS (Table 2, Method F) R t = 1.44 min; MS m/z: 567/569 [M+Na] + . (iii) 4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-3-(2-(methylamino)eth oxy)phenyl)pyrimidine- 2-carboxamide [000258] A mixture of tert-butyl (2-(3-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)- 2,4-dimethylphenoxy)ethyl)(methyl)carbamate (100 mg, 0.18 mmol) and 4N HCl in 1,4- dioxane (3 mL, 12 mmol), and the resulting mixture was stirred at RT for 1 h. The mixture was subjected to SCX-2 purification followed by reverse phase purification (Table 2, Method 6) to afford the title compound as a white solid (55 mg, 68%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.49 (s, 1H), 9.14 (d, J = 5.2 Hz, 1H), 7.92 (d, J = 5.2 Hz, 1H), 7.75 (d, J = 2.4 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.44 (dd, J = 8.4, 2.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 6.78 (d, J = 8.4 Hz, 1H), 4.34 (t, J = 4.4 Hz, 2H), 3.37 (t, J = 4.4 Hz, 2H), 2.76 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H). LC/MS (Table 2, Method F) R t = 1.11 min; MS m/z: 445/447 [M+H] + . Example 37.4-(2,5-Dichlorophenyl)-N-(4-(((2-hydroxyethyl)(methyl)ami no)methyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide formic acid salt [000259] A solution of 2-(methylamino)ethanol (CAS: 109-83-1, 34 mg, 0.48 mmol) and triethylamine (67 µL, 0.48 mmol) in MeCN (10 mL) at 0℃ was treated dropwise with a solution of N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5-dichloropheny l)pyrimidine-2- carboxamide (100 mg, 0.24 mmol) in MeCN (2 mL), and the resulting mixture was stirred at the RT for 16 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (25.9 mg, 23.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.52 (s, 1H), 9.09 (d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.46 (dd, J = 8.6, 2.5 Hz, 1H), 7.25 (s, 2H), 4.05 (s, 2H), 3.96 - 3.89 (m, 2H), 3.08 - 2.99 (m, 2H), 2.72 (s, 3H), 2.38 (s, 6H). LC/MS (Table 2, Method F) R t = 1.10 min; MS m/z: 459/461 [M+H] + . Example 38.4-(5-Chloro-2-ethoxyphenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000260] 1 H NMR (400 MHz, CDCl 3 ) δ 9.51 (s, 1H), 8.98 (d, J = 5.2 Hz, 1H), 8.23 (d, J = 5.2 Hz, 1H), 8.14 (d, J = 2.4 Hz, 1H), 7.44 (dd, J = 8.8, 2.4 Hz, 1H), 7.18 (s, 2H), 7.00 (d, J = 8.8 Hz, 1H), 4.68 (s, 2H), 4.19 (q, J = 6.8 Hz, 2H), 2.37 (s, 6H), 1.51 (t, J = 6.8 Hz, 3H). LC/MS (Table 2, Method F) R t = 1.27 min; MS m/z: 412/414 [M+H] + . Example 39.4-(2-Chloro-5-fluorophenyl)-N-(4-(hydroxymethyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000261] 1 H NMR (400 MHz, CDCl 3 ) δ 9.46 (s, 1H), 9.08 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 5.2 Hz, 1H), 7.57 - 7.53 (m, 2H), 7.23 - 7.19 (m, 1H), 7.18 (s, 2H), 4.68 (s, 2H), 2.36 (s, 6H). LC/MS (Table 2, Method F) R t = 1.21 min; MS m/z: 386/388 [M+H] + .. Example 40. N-(4-(Hydroxymethyl)-2,6-dimethylphenyl)-4-(2-methoxy-5- methylphenyl)pyrimidine-2-carboxamide [000262] 1 H NMR (400 MHz, CDCl 3 ) δ 9.58 (s, 1H), 8.93 (d, J = 4.9 Hz, 1H), 8.17 (d, J = 4.9 Hz, 1H), 7.93 (d, J = 1.8 Hz, 1H), 7.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.18 (s, 2H), 6.98 (d, J = 8.4 Hz, 1H), 4.68 (s, 2H), 3.94 (s, 3H), 2.41 (s, 3H), 2.37 (s, 6H). LC/MS (Table 2, Method F) R t = 1.33 min; MS m/z: 378 [M+H] + . Example 41.4-(2,5-Dichlorophenyl)-N-(4-(((2-hydroxyethyl)(methyl)ami no)methyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide formic acid salt [000263] A solution of 2-(methylamino)ethanol (CAS: 109-83-1, 34 mg, 0.48 mmol) and triethylamine (67 µL, 0.48 mmol) in MeCN (10 mL) at 0℃ was treated dropwise with a solution of N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5-dichloropheny l)pyrimidine-2- carboxamide (100 mg, 0.24 mmol) in MeCN (2 mL), and the resulting mixture was stirred at the RT for 16 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (25.9 mg, 23.5%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.52 (s, 1H), 9.09 (d, J = 5.2 Hz, 1H), 8.43 (s, 1H), 7.95 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 2.5 Hz, 1H), 7.52 (d, J = 8.6 Hz, 1H), 7.46 (dd, J = 8.6, 2.5 Hz, 1H), 7.25 (s, 2H), 4.05 (s, 2H), 3.96 - 3.89 (m, 2H), 3.08 - 2.99 (m, 2H), 2.72 (s, 3H), 2.38 (s, 6H). LC/MS (Table 2, Method F) R t = 1.10 min; MS m/z: 459/461 [M+H] + . Example 42.4-(2,5-Dichlorophenyl)-N-(4-(((2-hydroxyethyl)amino)methy l)-2,6- dimethylphenyl)pyrimidine-2-carboxamide formic acid salt [000264] The title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(4-(((2-hydroxyethyl)(methyl)amino) methyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide from the appropriate starting materials (N-(4- (chloromethyl)-2,6-dimethylphenyl)-4-(2,5-dichlorophenyl)pyr imidine-2-carboxamide and 2- aminoethanol (CAS: 141-43-5)). 1 H NMR (400 MHz, CDCl 3 ) δ 9.52 (s, 1H), 9.08 (d, J = 5.2 Hz, 1H), 8.41 (s, 1H), 7.94 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.4 Hz, 1H), 7.30 (s, 2H), 4.07 (s, 2H), 3.82 (s, 2H), 3.05 (s, 2H), 2.34 (s, 6H). LC/MS (Table 2, Method F) Rt = 1.09 min; MS m/z: 445/447 [M+H] + . Example 43. N-(4-(2,5-Dichlorophenyl)pyrimidin-2-yl)-4-(hydroxymethyl)-2 ,6- dimethylbenzamide (i) Methyl 4-((ethoxymethoxy)methyl)-2,6-dimethylbenzoate [000265] A mixture of methyl 4-(hydroxymethyl)-2,6-dimethylbenzoate (CAS: 113899-81- 3, 250 mg, 1.29 mmol) in DCM (5 mL) was treated with (chloromethoxy)ethane (CAS: 3188- 13-4, 239 µL, 2.58 mmol) and DIPEA (676 µL, 3.87 mmol), and the resulting mixture was stirred at RT for 2 h. The mixture was partitioned between DCM and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a yellow oil (300 mg, 92%). LC/MS (Table 2, Method F) R t = 1.50 min; MS m/z: 275 [M+Na] + . (ii) 4-((Ethoxymethoxy)methyl)-2,6-dimethylbenzoic acid [000266] A mixture of methyl 4-((ethoxymethoxy)methyl)-2,6-dimethylbenzoate (300 mg, 1.19 mmol), sodium hydroxide (476 mg, 11.9 mmol), MeOH (3 mL) and distilled water (3 mL) was heated at 60℃ for 20 h. The mixture was cooled to RT, adjusted to pH 3 with 1N HCl and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the title compound as a white solid (250 mg, 88%). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 261 [M+Na] + . (iii) 4-((Ethoxymethoxy)methyl)-2,6-dimethylbenzoyl chloride [000267] A mixture of 4-((ethoxymethoxy)methyl)-2,6-dimethylbenzoic acid (180 mg, 0.8 mmol) and DCM (2 mL) was treated with DMF (0.2 mL) and oxalyl chloride (103 µL, 1.2 mmol), and the resulting mixture was stirred at RT for 0.5 h. The mixture was concentrated in vacuo to afford the title compound as a yellow solid (194 mg, 100%.) which was used directly in the next reaction. LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 253 [M+H] + (methyl ester). (iv) 4-((Ethoxymethoxy)methyl)-2,6-dimethylbenzamide [000268] A solution of 4-((ethoxymethoxy)methyl)-2,6-dimethylbenzoyl chloride (194 mg, 0.76 mmol) in THF (4 mL) was treated with ammonia (0.4 M in THF, 3.0 mL) and the resulting mixture was stirred at RT for 1 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the title compound as a yellow oil (180 mg, 100%). LC/MS (Table 2, Method F) R t = 1.14 min; MS m/z: 238 [M+H] + . (v) N-(4-(2,5-Dichlorophenyl)pyrimidin-2-yl)-4-(hydroxymethyl)-2 ,6-dimethylbenzamide [000269] A mixture of 2-chloro-4-(2,5-dichlorophenyl)pyrimidine (CAS: 894854-15-0, 109 mg, 0.42 mmol), 4-((ethoxymethoxy)methyl)-2,6-dimethylbenzamide (100 mg, 0.42 mmol), tris(dibenzylideneacetone)dipalladium(0) (115 mg, 0.126 mmol), Xantphos (36 mg, 0.063 mmol), cesium carbonate (205 mg, 0.63 mmol) and 1,4-dioxane (3 mL) was degassed and placed under an atmosphere of argon before being heated at 100℃ for 24 h. The mixture was cooled to RT and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was treated with 4N HCl in dioxane (5 mL) and the resulting mixture was stirred at RT for 0.5 h. The mixture was adjusted to pH ~7 with a saturated aqueous sodium hydrogen carbonate solution and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ), concentrated in vacuo and purified by reverse phase HPLC (Table 2 Method 6) to afford the title compound (25 mg, 16%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.20 (s, 1H), 8.78 (s, 1H), 7.64 (m, 4H), 7.00 (s, 2H), 5.16 (s, 1H), 4.46 (d, J = 4.1 Hz, 2H), 2.23 (s, 6H). LC/MS (Table 2, Method E) R t = 1.34 min; MS m/z: 402/404 [M+H] + . Example 44.4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(hydroxymethyl)-6- methylphenyl)pyrimidine-2-carboxamide (i) 4-Amino-3-ethyl-5-methylbenzaldehyde [000270] A mixture of 2-ethyl-6-methylaniline (CAS: 24549-06-2, 2.0 g, 14.8 mmol) and hexamethylenetetramine (CAS: 100-97-0, 2.0 g, 14.8 mmol) in acetic acid (20 mL) and distilled water (5 mL) was set to stir at RT and next heated at 120℃ for 2 h. The reaction was cooled to RT, adjusted to pH ~3 with a saturated aqueous sodium hydrogen carbonate solution and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a white solid (1.5 g, 62%) as a white solid. LC/MS (Table 2, Method F) R t = 1.21 min; MS m/z: 164 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-formyl-6-methylphenyl)py rimidine-2-carboxamide [000271] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl) pyrimidine-2-carboxylic and 4-amino-3-ethyl-5-methylbenzaldehyde). LC/MS (Table 2, Method F) R t = 1.47 min; MS m/z: 414/416 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(hydroxymethyl)-6-methyl phenyl)pyrimidine-2- carboxamide [000272] A mixture of 4-(2,5-dichlorophenyl)-N-(2-ethyl-4-formyl-6- methylphenyl)pyrimidine-2-carboxamide (200 mg, 0.48 mmol) in MeOH (3 mL) at 0ºC was treated portionwise with sodium borohydride (54 mg, 1.44 mmol). The reaction was allowed to warm to RT and stirred at RT for 0.5 h. The reaction was partitioned between distilled water and ethyl acetate. The organic layer was separated, the combined organics were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (80 mg, 40%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.5 Hz, 1H), 7.10 (s, 2H), 5.17 (s, 1H), 4.48 (s, 2H), 2.58 (q, J = 7.5 Hz, 2H), 2.19 (s, 3H), 1.12 (t, J = 7.5 Hz, 3H). LC/MS (Table 2, Method F) R t = 1.38 min; MS m/z: 416/418 [M+H] + . Example 45. N-(4-(Aminomethyl)-2-ethyl-6-methylphenyl)-4-(2,5-dichloroph enyl)pyrimidine- 2-carboxamide (i) N-(4-(Chloromethyl)-2-ethyl-6-methylphenyl)-4-(2,5-dichlorop henyl)pyrimidine-2- carboxamide [000273] A mixture of 4-(2,5-dichlorophenyl)-N-(2-ethyl-4-(hydroxymethyl)-6- methylphenyl)pyrimidine-2-carboxamide (100 mg, 0.24 mmol) and CHCl 3 (2 mL) was treated with thionyl chloride (86 µL, 1.2 mmol), and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the title compound as a yellow solid (104 mg, 100%) which was used directly in the next reaction. LCMS (Table 2, Method E) R t = 1.57 min MS, m/z: 434/436 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(4-((1,3-dioxoisoindolin-2-yl)methy l)-2-ethyl-6- methylphenyl)pyrimidine-2-carboxamide [000274] A mixture of N-(4-(chloromethyl)-2-ethyl-6-methylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (100 mg, 0.23 mmol) and DMF (2 mL) was treated with potassium phthalimide (CAS: 1074-82-4, 85 mg, 0.46 mmol), and the resulting mixture was heated at 60℃ for 4 h. The mixture was cooled to RT and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo to afford the title compound as a white solid (100 mg, 80%). LCMS (Table 2, Method E) R t = 1.54min MS, m/z: 545/547 [M+H] + . (iii) N-(4-(Aminomethyl)-2-ethyl-6-methylphenyl)-4-(2,5-dichloroph enyl)pyrimidine-2- carboxamide [000275] A mixture of 4-(2,5-dichlorophenyl)-N-(4-((1,3-dioxoisoindolin-2-yl)methy l)-2- ethyl-6-methylphenyl)pyrimidine-2-carboxamide (100 mg, 0.18 mmol) and EtOH (3 mL) was treated with hydrazine monohydrate (88 µL, 1.8 mmol), and the resulting mixture was heated at 60℃ for 3 h. The mixture was cooled RT, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (45 mg, 59%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.37 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.36 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.99 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.22 (s, 1H), 7.21 (s, 1H), 3.91 (s, 2H), 2.59 (q, J = 7.5 Hz, 2H), 2.20 (s, 3H), 1.14 (t, J = 7.6 Hz, 3H). LC/MS (Table 2, Method F) R t = 1.18 min; MS m/z: 415/417 [M+H] + . Example 46.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4- ((methylamino)methyl)phenyl)pyrimidine-2-carboxamide formic acid salt [000276] A mixture of N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (120 mg, 0.29 mmol) EtOH (10 mL) and methylamine (33% wt in EtOH, 2.2 mL, 23.2 mmol) was stirred at RT for 6 h. The mixture was concentrated in vacuo and the residue purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (30.5 mg, 25%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.50 (s, 1H), 9.08 (d, J = 5.2 Hz, 1H), 8.46 (s, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.77 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 8.4, 2.4 Hz, 1H), 7.28 (s, 2H), 3.97 (s, 2H), 2.55 (s, 3H), 2.32 (s, 6H). LC/MS (Table 2, Method F) R t = 1.09 min; MS m/z: 415/417 [M+H] + . Example 47.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4- (morpholinomethyl)phenyl)pyrimidine-2-carboxamide [000277] A mixture of N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (120 mg, 0.29 mmol), THF (15 mL) and morpholine (75 µL, 0.87 mmol) heated at 75℃ for 5 h. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (29.5 mg, 22%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.47 (s, 1H), 9.08 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.4, 2.4 Hz, 1H), 7.16 (s, 2H), 3.82 (t, J = 4.4 Hz, 4H), 3.61 (s, 2H), 2.63 (br s, 4H), 2.35 (s, 6H). LC/MS (Table 1, Method F) R t = 1.09 min; MS m/z: 471/473 [M+H] + . Example 48.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-((3-oxopiperazin -1- yl)methyl)phenyl)pyrimidine-2-carboxamide [000278] A mixture of N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (120 mg, 0.29 mmol), EtOH (20 mL), piperazin- 2-one (46 mg, 0.46 mmol) and sodium carbonate (31 mg, 0.29 mmol) was heated at 80ºC for 5 h. The mixture was cooled to RT and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (38.8 mg, 27%). 1 H NMR (400 MHz, CDCl 3 ) δ 9.47 (s, 1H), 9.08 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 8.4, 2.4 Hz, 1H), 7.14 (s, 2H), 6.01 (s, 1H), 3.60 (s, 2H), 3.43 (s, 2H), 3.27 (s, 2H), 2.74 (s, 2H), 2.35 (s, 6H). LC/MS (Table 2, Method F) R t = 1.10 min; MS m/z: 484/486 [M+H] + . Example 49.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(((2,2,2- trifluoroethyl)amino)methyl)phenyl)pyrimidine-2-carboxamide [000279] The title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(2,6-dimethyl-4-((3-oxopiperazin-1- yl)methyl)phenyl)pyrimidine-2-carboxamide from the appropriate starting materials N-(4- (chloromethyl)-2,6-dimethylphenyl)-4-(2,5-dichlorophenyl)pyr imidine-2-carboxamide and 2,2,2-trifluoroethanamine (CAS: 753-90-2)). 1 H NMR (400 MHz, CDCl 3 ) δ 9.47 (s, 1H), 9.11 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.78 (d, J = 2.4 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.46 (dd, J = 8.4, 2.4 Hz, 1H), 7.21 (s, 2H), 4.00 (s, 2H), 3.31 (q, J = 9.1 Hz, 2H), 2.35 (s, 6H). LC/MS (Table 2, Method F) R t = 1.31 min; MS m/z: 483/485[M+H] + . Example 50.4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxypropan-2-yl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide (i) 2-(4-Amino-3,5-dimethylphenyl)propan-2-ol [000280] A solution of methyl 4-amino-3,5-dimethylbenzoate (CAS: 3095-48-5, 2.0 g, 11.2 mmol) in THF (30 mL) at 0℃ was treated dropwise CH 3 MgBr (3M in Et 2 O, 26 mL, 78 mmol), and the resulting mixture was heated at 70℃ for 2 h. The mixture was cooled to 0℃, diluted with a saturated aqueous of solution NH 4 Cl and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as an off-white solid (560 mg, 28%). LC/MS (Table 2, Method F) Rt = 0.88 min; MS m/z: 180 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxypropan-2-yl)-2,6-dimet hylphenyl)pyrimidine-2- carboxamide [000281] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic and 2-(4-amino-3,5-dimethylphenyl)propan-2-ol). 1 H NMR (400 MHz, DMSO-d 6 ): δ 10.26 (s, 1H), 9.15 (d, J = 4.0 Hz, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.99 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.67 (dd, J = 2.8 and 8.0 Hz, 1H), 7.22 (s, 2H), 4.99 (s, 1H), 2.2 (s, 6H), 1.43 (s, 6H). LC/MS (Table 2, Method F) R t = 1.32 min; MS m/z: 430/432[M+H] + . Example 51.4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxyethyl)-2,6-dimethyl phenyl)pyrimidine- 2-carboxamide (i) 2-(4-Amino-3,5-dimethylphenyl)ethan-1-ol [000282] A solution of methyl 2-(4-amino-3,5-dimethylphenyl)acetate (CAS: 2091304-52- 6, 100 mg, 0.52 mmol) in THF (5 mL) at 0ºC was treated with LiAlH 4 (62.4 mg, 1.56 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was cooled to 0ºC, diluted with a saturated aqueous solution of ammonium chloride and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo to give the title compound as a yellow solid (80 mg, 85%). LC/MS (Table 2, Method F) R t = 0.49 min; MS m/z: 166 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxyethyl)-2,6-dimethylphe nyl)pyrimidine-2- carboxamide [000283] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and 2-(4-amino-3,5-dimethylphenyl)ethan-1- ol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.5 Hz, 1H), 6.98 (s, 2H), 4.66 (t, J = 5.2 Hz, 1H), 3.62 - 3.57 (m, 2H), 2.68 (t, J = 7.0 Hz, 2H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.28 min; MS m/z: 416/418 [M+H] + . Example 52.4-(2,5-Dichlorophenyl)-N-(4-(3-hydroxypropyl)-2,6-dimethy lphenyl)pyrimidine- 2-carboxamide [000284] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and 3-(4-amino-3,5-dimethylphenyl) propan-1- ol (CAS: 454476-59-6)). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.24 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.5 Hz, 1H), 6.97 (s, 2H), 4.48 (s, 1H), 3.43 (t, J = 6.4 Hz, 2H), 2.61 (t, J = 7.8 Hz, 2H), 2.18 (s, 6H), 1.79 - 1.67 (m, 2H). LC/MS (Table 2, Method E) R t = 1.40 min; MS m/z: 430/432 [M+H] + . Example 53.4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2-(methylamino) -2- oxoethyl)phenyl)pyrimidine-2-carboxamide (i) Methyl 2-(4-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)-3,5-di methylphenyl)acetate [000285] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and methyl 2-(4-amino-3,5- dimethylphenyl)acetate). LC/MS (Table 2, Method F) R t = 1.37 min; MS m/z: 444/446 [M+H] + . (ii) 2-(4-(4-(2,5-Dichlorophenyl)pyrimidine-2-carboxamido)-3,5-di methylphenyl)acetic acid [000286] A solution of methyl 2-(4-(4-(2,5-dichlorophenyl)pyrimidine-2-carboxamido)- 3,5-dimethylphenyl)acetate (220 mg, 0.50 mmol) in a mixture MeOH (5 mL) and distilled water (2 mL) was treated with sodium hydroxide (180 mg, 4.5 mmol), and the resulting mixture was stirred at RT for 16 h. The mixture was concentrated in vacuo, adjusted to pH 5 with 1N HCl and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo to afford the title compound (200 mg, 83%). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 430/432 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(2,6-dimethyl-4-(2-(methylamino)-2- oxoethyl)phenyl)pyrimidine-2-carboxamide [000287] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (2-(4-(4- (2,5-dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylph enyl)acetic acid and methylamine hydrochloride (CAS: 593-51-1)). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.95 (q, J = 4.6 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 2.5 Hz, 1H), 7.01 (s, 2H), 3.34 (s, 2H), 2.58 (d, J = 4.6 Hz, 3H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.21 min; MS m/z: 443/445[M+H] + . Example 54.4-(2,5-Dichlorophenyl)-N-(4-(2-(dimethylamino)-2-oxoethyl )-2,6- dimethylphenyl)pyrimidine-2-carboxamide [000288] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (2-(4-(4- (2,5-dichlorophenyl)pyrimidine-2-carboxamido)-3,5-dimethylph enyl)acetic acid and 2M dimethylamine in THF (CAS: 124-40-3)). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.29 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.5 Hz, 1H), 6.99 (s, 2H), 3.64 (s, 2H), 3.03 (s, 3H), 2.84 (s, 3H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.26 min; MS m/z: 457/459 [M+H] + . Example 55.4-(2,5-Dichlorophenyl)-N-(4-(2-(dimethylamino)ethyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide formic acid salt (i) N-(4-(2-chloroethyl)-2,6-dimethylphenyl)-4-(2,5-dichlorophen yl)pyrimidine-2- carboxamide [000289] A solution of 4-(2,5-dichlorophenyl)-N-(4-(2-hydroxyethyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide (100 mg, 0.24 mmol) in CHCl 3 (5 mL) was treated with thionyl chloride (87 µL, 1.2 mmol) and triethylamine (50 µL, 0.36 mmol), and the resulting mixture was heated at 50℃ for 5 h. The mixture was cooled to RT and concentrated in vacuo to afford the title compound (104 mg, 100%) which was used directly in the next reaction. (ii) 4-(2,5-Dichlorophenyl)-N-(4-(2-(dimethylamino)ethyl)-2,6-dim ethylphenyl)pyrimidine- 2-carboxamide formic acid salt [000290] A solution of N-(4-(2-chloroethyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (100 mg, 0.23 mmol) in DMF (2 mL) was treated with potassium carbonate (158.7 mg, 1.15 mmol), potassium iodide (3.8 mg, 0.02 mmol) and 2M dimethylamine in THF (CAS: 124-40-3, 0.3 mL, 1.15 mmol), and the resulting mixture was heated at 100ºC for 24 h. The reaction was cooled to RT and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a light-yellow solid (31 mg, 8%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.26 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.21 (s, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.4 Hz, 1H), 7.74 (d, J = 8.8 Hz, 1H), 7.69 (dd, J = 8.8, 2.4 Hz, 1H), 6.99 (s, 2H), 2.71 (t, J = 7.0, 2H), 2.59 (t, J = 7.0 Hz, 2H), 2.27 (s, 6H), 2.18 (s, 6H). LC/MS (Table 2, Method F) R t = 1.13 min; MS m/z: 443/445 [M+H] + . Example 56.4-(2,5-Dichlorophenyl)-N-(4-((dimethylamino)methyl)-2,6- dimethylphenyl)pyrimidine-2-carboxamide formic acid salt [000291] A solution of N-(4-(chloromethyl)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (100 mg, 0.24 mmol) in CHCl 3 (10 mL) was treated with 2M dimethylamine in THF (CAS: 124-40-3, 6.2 mL), and the resulting mixture was heated at 50℃ for 2 h. The mixture was cooled RT and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (49 mg, 47%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.33 (s, 1H), 9.16 (d, J = 5.2 Hz, 1H), 8.14 (s, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.6 Hz, 1H), 7.68 (dd, J = 8.6, 2.5 Hz, 1H), 7.11 (s, 2H), 3.54 (s, 2H), 2.30 (s, 6H), 2.21 (s, 6H). LC/MS (Table 2, Method F) R t = 1.09 min; MS m/z: 429/431 [M+H] + . Example 57.4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(2-hydroxyethoxy)-6- methylphenyl)pyrimidine-2-carboxamide (i) Ethyl 2-(4-amino-3-ethyl-5-methylphenoxy)acetate [000292] A solution of 4-amino-3-ethyl-5-methylphenol (CAS: 112730-54-8, 1.0 g, 6.6 mmol) in MeCN (50 mL) at 0℃ was treated with ethyl 2-bromoacetate (CAS: 105-36-2, 728 µL, 6.6 mmol) and cesium carbonate (4.74 g, 14.5 mol), and the resulting mixture was stirred at RT for 24 h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a yellow solid (0.82 g, 53.0%). LC/MS (Table 2, Method F) R t = 1.20 min; MS m/z: 238 [M+H] + . (ii) 2-(4-Amino-3-ethyl-5-methylphenoxy)ethan-1-ol [000293] A solution of ethyl 2-(4-amino-3-ethyl-5-methylphenoxy)acetate (820 mg, 3.46 mmol) in THF (30 mL) at 0ºC was treated with LiAlH 4 (276 mg, 7.27 mmol), and the resulting mixture was stirred at RT for 24 h. The mixture was cooled to 0ºC and diluted with MeOH and a 10% aqueous sodium hydroxide solution, and the resulting mixture was concentrated in vacuo. The residue was adjusted to pH ~6 with 2N HCl and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a brown oil (330 mg, 49%). LC/MS (Table 2, Method F) R t = 0.48 min; MS m/z: 196 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(2-hydroxyethoxy)-6-meth ylphenyl)pyrimidine-2- carboxamide [000294] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and 2-(4-amino-3-ethyl-5- methylphenoxy)ethan-1-ol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 9.15 (d, J = 5.2 Hz, 1H), 8.11 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 2.5 Hz, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.68 (dd, J = 8.0, 2.5 Hz, 1H), 6.73 (d, J = 2.7 Hz, 1H), 6.70 (d, J = 2.7 Hz, 1H), 4.87 (s, 1H), 3.99 (t, J = 5.0 Hz, 2H), 3.72 (t, J = 5.0 Hz, 2H), 2.56 (q, J = 7.5 Hz, 2H), 2.17 (s, 3H), 1.11 (t, J = 7.5 Hz, 3H). LC/MS (Table 2, Method F) R t = 1.32 min; MS m/z: 446/448 [M+H] + . Example 58.4-(2,5-Dichlorophenyl)-N-(4-(3-hydroxypropoxy)-2,6- dimethylphenyl)pyrimidine-2-carboxamide (i) 3-(4-Amino-3,5-dimethylphenoxy)propan-1-ol [000295] A mixture of 4-amino-3,5-dimethylphenol (CAS: 3096-70-6, 1.0 g, 7.3 mmol), cesium carbonate (7.1 g, 21.9 mmol) and DMF (50 mL) was treated dropwise 3- chloropropan-1-ol (1.2 mL, 14.6 mmol), and the resulting mixture was heated at 100℃ for 1 h. The mixture was cooled to RT and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title compound as a light yellow solid (1.06 g, 74%). LC/MS (Table 2, Method F) R t = 0.58 min; MS m/z: 196 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(4-(3-hydroxypropoxy)-2,6-dimethylp henyl)pyrimidine-2- carboxamide [000296] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and 3-(4-amino-3,5-dimethylphenoxy)propan- 1-ol). 1 H NMR (400 MHz, CDCl 3 ) δ 9.35 (s, 1H), 9.08 (d, J = 5.2 Hz, 1H), 7.93 (d, J = 5.2 Hz, 1H), 7.79 (d, J = 2.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.47 (dd, J = 8.0, 2.0 Hz, 1H), 6.72 (s, 2H), 4.15 (t, J = 5.9 Hz, 2H), 3.89 (t, J = 5.9 Hz, 2H), 2.31 (s, 6H), 2.12 - 2.02 (m, 2H). LC/MS (Table 2, Method F) R t = 1.29 min; MS m/z: 446/448 [M+H] + . Example 59.4-(2-Chloro-5-isopropylphenyl)-N-(4-(2-hydroxyethoxy)-2,6 - dimethylphenyl)picolinamide (i) 4-(2-Chloro-5-isopropylphenyl)picolinic acid [000297] A mixture of 4-bromopyridine-2-carboxylic acid (CAS: 30766-03-1, 430 mg, 2.13 mmol), (2-chloro-5-isopropylphenyl)boronic acid (CAS: 875550-89-3, 500 mg, 2.56 mmol), trans-dichlorobis(triphenylphosphine)palladium(II) (150 mg, 0.213 mmol), sodium carbonate (680 mg, 6.39 mmol), 1,4-dioxane (15 mL) and distilled water (5 mL) was degassed and placed under an atmosphere of argon before being heated at 100℃ for 3 h. The mixture was cooled to RT, adjusted to pH ~4 with 1N HCl and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo to afford the title compound as a white solid (589 mg, 100%). LC/MS (Table 2, Method F) R t = 1.25 min; MS m/z: 276 [M+H] + . (ii) 4-(2-Chloro-5-isopropylphenyl)picolinoyl chloride [000298] A solution of 4-(2-chloro-5-isopropylphenyl)picolinic acid (210 mg, 0.76 mmol) in DCM (6 mL ) at 0ºC was treated with SOCl 2 (118 µL, 1.52 mmol) and DMF (10 µL), and the resulting mixture was stirred at RT for 0.5 h. The mixture was concentrated in vacuo to afford the title compound as an off-white solid (224 mg, 100%). LC/MS (Table 2, Method F) R t = 1.45 min; MS m/z: 290 [M+H] + (Me ester). (iii) 4-(2-Chloro-5-isopropylphenyl)-N-(4-(2-hydroxyethoxy)-2,6- dimethylphenyl)picolinamide [000299] A solution of 4-(2-chloro-5-isopropylphenyl)picolinoyl chloride (210 mg, 0.71 mmol) in THF (8 mL) was treated with 2-(4-amino-3,5-dimethylphenoxy)ethanol (CAS: 1314211-90-9, 130 mg, 0.71 mmol) and DIPEA (372 µL, 2.13 mmol), and the resulting mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as white solid (123 mg, 39%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.13 (s, 1H), 8.82 (d, J = 5.0 Hz, 1H), 8.12 (s, 1H), 7.77 (d, J = 5.0 Hz, 1H), 7.56 (d, J = 8.1 Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.37 (dd, J = 8.1, 2.5 Hz, 1H), 6.71 (s, 2H), 4.87 (t, J = 5.1 Hz, 1H), 3.97 (t, J = 5.1 Hz, 2H), 3.72-3.69 (m, 2H), 2.98 (sept, J = 6.9 Hz, 1H), 2.15 (s, 6H), 1.24 (d, J = 6.9 Hz, 6H). LC/MS (Table 2, Method B) R t = 1.49 min; MS m/z: 439/441[M+H] + . Example 60.4-(2,5-Dichlorophenyl)-N-(4-(3-hydroxypropoxy)-2,6- dimethylphenyl)picolinamide (i) 4-(2,5-Dichlorophenyl)picolinoyl chloride [000300] A solution of 4-(2,5-dichlorophenyl)picolinic acid (1.5 g, 5.6 mmol) in DCM (30 mL) at 0℃ was treated dropwise with oxalyl chloride (1.4 mL, 16.8 mmol) and DMF (10 µL), and the resulting mixture was stirred at RT for 1 h. The mixture was concentrated in vacuo to afford the title compound as a red solid (1.59 g, 98%). LC/MS (Table 2, Method F) R t = 1.32 min; MS m/z: 282/284 [M+H] + (Me ester). (ii) 4-(2,5-Dichlorophenyl)-N-(4-(3-hydroxypropoxy)-2,6-dimethylp henyl)picolinamide [000301] A solution of 4-(2,5-dichlorophenyl)picolinoyl chloride (730 mg, 2.56 mmol) and 3-(4-amino-3,5-dimethylphenoxy)propan-1-ol (500 mg, 2.56 mmol) in THF (50 mL) at 0℃ was treated with DIPEA (1.27 mL, 7.68 mmol), and the resulting mixture was stirred at RT for 2 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound (1.1 g, 96%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.37 (s, 1H), 7.64 (d, J = 4.9 Hz, 1H), 7.55 - 7.32 (m, 3H), 6.72 (s, 2H), 4.15 (t, J = 5.8 Hz, 2H), 3.89 (t, J = 5.8 Hz, 2H), 2.30 (s, 6H), 2.12 - 2.02 (m, 2H). LC/MS (Table 2, Method F) R t = 1.42 min; MS m/z: 445/ 447 [M+H] + . Example 61.4-(2,5-Dichlorophenyl)-N-(2-ethyl-4-(2-hydroxyethoxy)-6- methylphenyl)picolinamide [000302] A solution of 4-(2,5-dichlorophenyl)picolinoyl chloride (265 mg, 0.92 mmol) and 2-(4-amino-3-ethyl-5-methylphenoxy)ethan-1-ol (150 mg, 0.77 mmol) in THF (50 mL) at 0℃ was treated with DIPEA (380 µL, 2.31 mmol), and the resulting mixture was stirred at the RT for 2 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a light-yellow solid (230 mg, 67 %). 1 H NMR (400 MHz, CDCl 3 ) δ 9.43 (s, 1H), 8.73 (d, J = 4.9 Hz, 1H), 8.37 (s, 1H), 7.65 (d, J = 4.9 Hz, 1H), 7.49 (d, J = 2.5 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.39 (dd, J = 8.0, 2.5 Hz, 1H), 6.75 (d, J = 4.4 Hz, 2H), 4.13 (t, J = 4.4 Hz, 2H), 3.99 (t, J = 4.4 Hz, 2H), 2.66 (q, J = 7.5 Hz, 2H), 2.31 (s, 3H), 1.23 (t, J = 7.5 Hz, 3H). LC/MS (Table 2, Method B) R t = 1.42 min; MS m/z: 445/447 [M+H] + . Example 62. N-(4-(2-Aminoethoxy)-2,6-dimethylphenyl)-4-(2,5-dichlorophen yl)picolinamide formic acid salt (i) 4-(2,5-Dichlorophenyl)-N-(4-(2-hydroxyethoxy)-2,6-dimethylph enyl)picolinamide [000303] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)picolinic acid and 2-(4-amino-3,5-dimethylphenoxy)ethanol (CAS: 1314211- 90-9)). LC/MS (Table 2, Method F) R t = 1.34 min; MS m/z: 431/433 [M+H] + . (ii) N-(4-(2-chloroethoxy)-2,6-dimethylphenyl)-4-(2,5-dichlorophe nyl)picolinamide [000304] A solution of 4-(2,5-dichlorophenyl)-N-(4-(2-hydroxyethoxy)-2,6- dimethylphenyl)picolinamide (150 mg, 0.35 mmol) in DCM (20 mL) at 0℃ was treated with thionyl chloride (60 µL, 0.80 mmol) and pyridine (70 µL, 0.84 mmol), and the resulting mixture was stirred at RT for 24 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40- 60ºC:EtOAc, 70:30) to afford the title compound as a yellow oil (156 mg, 100%). LC/MS (Table 2, Method F) Rt = 1.50 min; MS m/z: 449/451 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(4-(2-(1,3-dioxoisoindolin-2-yl)eth oxy)-2,6- dimethylphenyl)picolinamide [000305] A solution of N-(4-(2-chloroethoxy)-2,6-dimethylphenyl)-4-(2,5- dichlorophenyl)picolinamide (156 mg, 0.35 mmol) in DMF (10 mL) was treated with potassium phthalimide (CAS: 1074-82-4, 79 mg, 0.43 mmol), and the resulting mixture was stirred at RT for 16 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, 50:50) to afford the title compound as a light yellow oil (55 mg, 28%). LC/MS (Table 2, Method F) R t = 1.54 min; MS m/z: 560/562 [M+H] + . (iv) N-(4-(2-Aminoethoxy)-2,6-dimethylphenyl)-4-(2,5-dichlorophen yl)picolinamide formic acid salt [000306] A solution of 4-(2,5-dichlorophenyl)-N-(4-(2-(1,3-dioxoisoindolin-2-yl)eth oxy)- 2,6-dimethylphenyl)picolinamide (55 mg, 0.10 mmol) in THF (10 mL) was treated with hydrazine hydrate (150 µL, 3 mmol), and the resulting mixture was heated at 65ºC for 24 h. The mixture was cooled to RT and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (21 mg, 47%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 (s, 1H), 8.84 (d, J = 5.1 Hz, 1H), 8.36 (s, 1H), 8.14 (d, J = 1.1 Hz, 1H), 7.79 (dd, J = 5.0, 1.8 Hz, 1H), 7.72 -7.67 (m, 2H), 7.61 (dd, J = 8.6, 2.5 Hz, 1H), 6.73 (s, 2H), 4.03 (t, J = 5.4 Hz, 2H), 3.03 (t, J = 5.4 Hz, 2H), 2.16 (s, 6H). LC/MS (Table 2, Method F) R t = 1.20 min; MS m/z: 430/432 [M+H] + . Example 63.4-(2,5-Dichlorophenyl)-N-(1,4-dimethyl-1H-pyrazol-5-yl)py rimidine-2- carboxamide [000307] The title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(2,6-dimethyl-3- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5-dichlorophenyl)pyrimidine-2-carbonyl chloride and 1,4-dimethyl-1H-pyrazol-5- amine (CAS: 1192-21-8)). 1 H NMR (400 MHz, CD 3 OD) δ 9.13 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.37 (s, 1H), 3.76 (s, 3H), 2.02 (s, 3H). LC/MS (Table 1, Method F) R t = 1.24 min; MS m/z: 362/364[M+H] + . Example 64.4-(2,5-Dichlorophenyl)-N-(1-(difluoromethyl)-3,5-dimethyl -1H-pyrazol-4- yl)pyrimidine-2-carboxamide [000308] The title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(2,6-dimethyl-3- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5-dichlorophenyl)pyrimidine-2-carbonyl chloride and 1-(difluoromethyl)-3,5-dimethyl- 1H-pyrazol-4-amine (CAS: 1005633-15-7)). 1 H NMR (400 MHz, CD 3 OD) 9.11 (d, J = 5.2 Hz, 1H), 8.10 (d, J = 5.2 Hz, 1H), 7.96 (d, J = 2.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.59 (dd, J = 8.8 Hz, 2.4 Hz, 1H), 7.56 (t, J = 58 Hz, 1H), 2.39 (s, 3H), 2.22 (s, 3H). LC/MS (Table 1, Method F) R t = 1.30 min; MS m/z: 411.6/413.6 [M+H] + . Example 65.4-(2,5-Dichlorophenyl)-N-(6-(hydroxymethyl)-2,4-dimethylp yridin-3- yl)pyrimidine-2-carboxamide (i) Methyl 5-amino-4,6-dimethylpicolinate [000309] A solution of 6-bromo-2,4-dimethylpyridin-3-amine (CAS: 897733-12-9, 400 mg, 1.99 mmol) in MeOH (5 mL) was treated with Pd(dppf)Cl 2 (145.61 mg, 0.199 mmol) and Et 3 N (831 µL, 5.97 mmol), and the resulting mixture was degassed and placed under an atmosphere of carbon monoxide before being heated at 100℃ for 5 h. The mixture was cooled to RT, filtered through celite and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (petroleum spirit 40-60ºC to petroleum spirit 40-60ºC:EtOAc, gradient elution) to afford the title (200 mg, 54%). LC/MS (Table 1, Method F) R t = 0.46 min; MS m/z: 181 [M+H] + . (ii) (5-Amino-4,6-dimethylpyridin-2-yl)methanol [000310] A solution of methyl 5-amino-4,6-dimethylpicolinate (70 mg, 0.39 mmol) in THF (5 mL) at 0℃ was treated with LiAlH 4 (28.1 mg, 0.70 mmol) and the resulting mixture was stirred at RT for 1 h. The mixture was diluted with a saturated aqueous ammonium chloride solution and extracted with EtOAc. The combined extracts were dried (MgSO 4 ) and concentrated in vacuo to give the title compound as a yellow solid (60 mg, 91%). LC/MS (Table 1, Method F) R t = 0.19 min; MS m/z: 153 [M+H] + . (iii) 4-(2,5-Dichlorophenyl)-N-(6-(hydroxymethyl)-2,4-dimethylpyri din-3-yl)pyrimidine-2- carboxamide [000311] The title compound was prepared by using an analogous reaction protocol as described for 4-(2,5-dichlorophenyl)-N-(2,6-dimethyl-3- (methylcarbamoyl)phenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5-dichlorophenyl)pyrimidine-2-carbonyl chloride and (5-amino-4,6-dimethylpyridin-2- yl)methanol). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.51 (s, 1H), 9.18 (d, J = 5.2 Hz, 1H), 8.13 (d, J = 5.2 Hz, 1H), 7.98 (d, J = 2.4 Hz, 1H), 7.71 - 7.64 (m, 2H), 7.26 (s, 1H), 5.39 (s, 1H), 4.52 (s, 2H), 2.37 (s, 3H), 2.23 (s, 3H). LC/MS (Table 1, Method F) R t = 1.07 min; MS m/z: 403/405 [M+H] + . Example 66.4-(2,5-Dichlorophenyl)-N-(5-(hydroxymethyl)-2,4-dimethylp henyl)pyrimidine-2- carboxamide [000312] The title compound was prepared by using an analogous reaction protocol as described for N-(4-(((tert-butyldimethylsilyl)oxy)methyl)-2,6-dimethylphen yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide from the appropriate starting materials (4-(2,5- dichlorophenyl)pyrimidine-2-carboxylic acid and (5-amino-2,4-dimethylphenyl)methanol (CAS: 1334148-06-9)). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 9.17 (d, J = 5.2 Hz, 1H), 8.12 (d, J = 5.2 Hz, 1H), 8.00 (d, J = 2.5 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 7.69 (dd, J = 8.6, 2.5 Hz, 1H), 7.67 (s, 1H), 7.06 (s, 1H), 5.11 (t, J = 5.4 Hz, 1H), 4.48 (d, J = 5.4 Hz, 2H), 2.24 (s, 3H), 2.22 (s, 3H). LC/MS (Table 1, Method F) R t = 1.46 min; MS m/z: 402/404 [M+H] + . Example 67. N-(6-(Aminomethyl)-2,4-dimethylpyridin-3-yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (i) N-(6-(Chloromethyl)-2,4-dimethylpyridin-3-yl)-4-(2,5-dichlor ophenyl)pyrimidine-2- carboxamide [000313] A solution of 4-(2,5-dichlorophenyl)-N-(6-(hydroxymethyl)-2,4-dimethylpyri din- 3-yl)pyrimidine-2-carboxamide (60 mg, 0.15 mmol) in CHCl 3 (2 mL) at 0ºC was treated with thionyl chloride (49 µL, 0.75 mmol) and the resulting mixture was stirred at RT for 2 h. The mixture was concentrated in vacuo to afford the title compound (63 mg, 100%) which was used directly in the next reaction. LC/MS (Table 1, Method F) R t = 1.314 min; MS m/z: 421, 423 [M+H] + . (ii) 4-(2,5-Dichlorophenyl)-N-(6-((1,3-dioxoisoindolin-2-yl)methy l)-2,4-dimethylpyridin-3- yl)pyrimidine-2-carboxamide [000314] A mixture of N-(6-(chloromethyl)-2,4-dimethylpyridin-3-yl)-4-(2,5- dichlorophenyl)pyrimidine-2-carboxamide (60 mg, 0.14 mmol) and DMF (2 mL) was treated with potassium phthalimide (CAS: 1074-82-4, 85 mg, 0.46 mmol), and the resulting mixture was heated at 70℃ for 2h. The mixture was cooled to RT and partitioned between EtOAc and distilled water. The organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by preparative TLC (petroleum spirit 40-60ºC to petroleum spirit 40- 60ºC:EtOAc, gradient elution) to afford the title compound as a light yellow solid (66 mg, 87%). LC/MS (Table 1, Method f) Rt = 1.34 min; MS m/z: 532/534 [M+H] + . (iii) N-(6-(Aminomethyl)-2,4-dimethylpyridin-3-yl)-4-(2,5-dichloro phenyl)pyrimidine-2- carboxamide [000315] A mixture of 4-(2,5-dichlorophenyl)-N-(6-((1,3-dioxoisoindolin-2-yl)methy l)- 2,4-dimethylpyridin-3-yl)pyrimidine-2-carboxamide (66 mg, 0.12 mmol) and EtOH (2 mL) was treated with hydrazine monohydrate (60 1.2 mmol), and the resulting mixture was heated at 70℃ for 2 h. The mixture was cooled to RT, filtered and the filtrate concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (15 mg, 27%). 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.57 (s, 1H), 9.18 (d, J = 5.2 Hz, 1H), 8.33 (s, 1H), 8.14 (d, J = 5.2 Hz, 1H), 7.97 (d, J = 2.5 Hz, 1H), 7.75 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 8.8, 2.4 Hz, 1H), 7.27 (s, 1H), 3.93 (s, 2H), 2.41 (s, 3H), 2.23 (s, 3H). LC/MS (Table 1, Method F) R t = 1.07 min; MS m/z: 402/404 [M+H] + . Example 68. N-(4-(Hydroxymethyl)-2,6-dimethylphenyl)-4-(thiazol-2-yl)pyr imidine-2- carboxamide (i) 4-(Thiazol-2-yl)pyrimidine-2-carboxylic acid [000316] A suspension of selenium dioxide (665.8 mg, 6.0 mmol) in pyridine (5 mL) was treated with 2-methyl-4-(1,3-thiazol-2-yl)pyrimidine (CAS: 1269291-29-3, 177 mg, 1.0 mmol) and the resulting mixture was heated at reflux for 16 h. The mixture cooled to RT, filtered and the filtrate concentrated in vacuo. The residue was purified by flash column chromatography (DCM to DCM:MeOH, gradient elution) to afford the title compound as a yellow solid (80 mg, 38%). LC/MS (Table 1, Method F) R t = 0.85 min; MS m/z: 208 [M+H] + . (ii) 4-(Thiazol-2-yl)pyrimidine-2-carbonyl chloride [000317] Oxalyl chloride (100 µL, 1.2 mmol) followed by DMF (10-20 µL) was added to a solution of 4-(thiazol-2-yl)pyrimidine-2-carboxylic acid (80 mg, 0.4 mmol) in THF (10 mL) at 0ºC and the resulting mixture was stirred at RT for 5 h. The mixture was concentrated in vacuo to afford the title compound (87 mg, 100%) which was used directly in the next reaction. LC/MS (Table 1, Method F) R t = 1.04 min; MS m/z: 222 [M+H] + (methyl ester). (iii) N-(4-(hydroxymethyl)-2,6-dimethylphenyl)-4-(thiazol-2-yl)pyr imidine-2-carboxamide [000318] A solution of 4-(thiazol-2-yl)pyrimidine-2-carbonyl chloride (86.9 mg, 0.39 mmol) in THF (10 mL) at 0ºC was treated sequentially with 4-amino-3,5- dimethylphenyl)methanol (CAS: 89210-26-4, 65.3 mg, 0.43 mmol) and triethylamine (100 µL, 1.08 mmol), and the resulting mixture was stirred at RT for 4 h. The mixture was partitioned between EtOAc and distilled water, and the organic layer was dried (MgSO 4 ) and concentrated in vacuo. The residue was purified by reverse phase HPLC (Table 2, Method 6) to afford the title compound as a white solid (20 mg, 16%) as a white powder. 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.28 (s, 1H), 9.16 (d, J = 4.0 Hz, 1H), 8.30 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 4.0 Hz, 1H), 7.08 (s, 2H), 5.16 (brs 1H), 4.47 (s, 2H), 2.22 (s, 6H). LC/MS (Table 1, Method F) R t = 1.08 min; MS m/z: 341 [M+H] + . Example 69. PATHHUNTER® β-Arrestin Assay [000319] S1PR4 antagonism was identified by screening compounds in the PathHunter® CHO-K1 EDG6 β-Arrestin Cell Line (93-0227C2, DiscoverX), using the PathHunter Detection Kit (93-001, DiscoverX), according to the manufacturer’s user manual. [000320] PathHunter® CHO-K1 EDG6 β-Arrestin cells (10000 cells/well (20µl/well) in a white, tissue cultured treated 384 well plate) were seeded in AssayComplete™ Cell Plating 11 Reagent (93-0563R11A, DiscoverX) and incubated overnight at 37˚C, 5% CO 2 . [000321] The PathHunter® CHO-K1 EDG6 β-Arrestin cells were pre-incubated for 30 minutes with a concentration range of test compounds (addition: 2.5 µL of 10X) at 37 ˚C, 5% CO 2 before addition of Sphingosine 1-phosphate (2.5 µL of 100 µM, final assay concentration: 10 µM) for 3 hours (37 ˚C, 5% CO2 for 150 minutes and room temperature for 30 minutes). [000322] PathHunter® Working Detection Solution was prepared as the manufacturer’s user manual. 12.5 µL of PathHunter® Working Detection Solution was added to all the wells in the assay plate and incubated at room temperature for 1 hour in the dark. Luminescence was read on the PheraSTAR plate reader (0.2 sec/well). [000323] IC 50 data are reported in Table 5 for compounds in Table 1. In Table 5 below, A indicates a B-arrestin IC 50 (µM) 0.01 µM to < 0.1 µM, B indicates a β -arrestin IC 50 (µM) 0.1 µM to < 1.0 µM, C indicates a B-arrestin IC 50 (µM) 1.0 µM to ≤ 10 µM, and D indicates a B-arrestin IC 50 (µM) 10 < µM. Table 5.
EQUIVALENTS AND SCOPE [000324] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [000325] Furthermore, the invention encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements and/or features, certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [000326] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the invention can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [000327] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.