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Documents Numérisés Par Onetouch 19 ORGANISATION AFRICAINE DE LA PROPRIETE INTELLECTUELLE 51 8 Inter. CI. C07D 471/04 (2018.01) 11 A61K 31/519 (2018.01) N° 18435 A61P 29/00 (2018.01) A61P 31/12 (2018.01) A61P 35/00 (2018.01) FASCICULE DE BREVET D'INVENTION A61P 37/00 (2018.01) 21 Numéro de dépôt : 1201700355 73 Titulaire(s): PCT/US2016/020499 GILEAD SCIENCES, INC., 333 Lakeside Drive, 22 Date de dépôt : 02/03/2016 FOSTER CITY, CA 94404 (US) 30 Priorité(s): Inventeur(s): 72 US n° 62/128,397 du 04/03/2015 CHIN Gregory (US) US n° 62/250,403 du 03/11/2015 METOBO Samuel E. (US) ZABLOCKI Jeff (US) MACKMAN Richard L. (US) MISH Michael R. (US) AKTOUDIANAKIS Evangelos (US) PYUN Hyung-jung (US) 24 Délivré le : 27/09/2018 74 Mandataire: GAD CONSULTANTS SCP, B.P. 13448, YAOUNDE (CM). 45 Publié le : 15.11.2018 54 Titre: Toll like receptor modulator compounds. 57 Abrégé : The present disclosure relates generally to toll like receptor modulator compounds, such as diamino pyrido [3,2 D] pyrimidine compounds and pharmaceutical compositions which, among other things, modulate toll-like receptors (e.g. TLR-8), and methods of making and using them. O.A.P.I. – B.P. 887, YAOUNDE (Cameroun) – Tel. (237) 222 20 57 00 – Site web: http:/www.oapi.int – Email: [email protected] 18435 TOLL LIKE RECEPTOR MODULATOR COMPOUNDS CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. Provisional Application Nos. 62/128397, filed March 4, 2015, and 62/250403, filed November 3, 2015, both of which are incorporated herein in their entireties for all purposes. FIELD 100021 This application relates generally to toll like receptor modulator compounds, including diamino pyrido[3,2 D] pyrimidine compounds, and pharmaceutical compositions which, among other things, modulate toll-like receptors (e g. TLR-8), and methods of making and using them. BACKGROUND [0003] The toll-like receptor (TLR) family plays a fundamental role in pathogen recognition and activation of innate immunity. Toll-like receptor 8 (TLR-8) is predominantly expressed by myeloid immune cells and activation of this receptor stimulates a broad immunological response. Agonists of TLR-8 activate myeloid dendritic cells, monocytes, monocyte-derived dendridic cells and Kupffer cells leading to the production of proinflammatory cytokines and chemokines, such as interleukin-18 (IL-18), interleukin- 12 (IL-12), tumor necrosis factor-alpha (TNF-a), and interferon- gamma (IFN-y). Such agonists also promote the increased expression of co-stimulatory molecules such as CDS + cells, major histocompatibility complex molecules (MAIT, NK cells), and chemokine receptors. [0004] Collectively, activation of these innate and adaptive immune responses induces an immune response and provides a therapeutic benefit in various conditions involving autoimmunity, inflammation, allergy, asthma, graft rejection, graft versus host disease (GvHD), infection, cancer, and immunodeficiency. For example, with respect to hepatitis B, activation of TLR8 on professional antigen presenting cells (pAPCs) and other intrahepatic immune cells is associated with induction of IL-12 and proinflammatory cytokines, which is expected to augment HBV-specific T cell responses, activate intrahepatic NK cells and drive reconstitution of antiviral immunity. See e.g. Wille-Reece, U. et al. JErpMed2O3, 1249-1258 (2006); Peng, G. et al., 1 18435 Science 309, 1380-1384 (2005); Jo, J. elaL, PLoS Pathogens 10, e1004210 (2014) and Watashi, K. et al., filial Chem 288, 31715-31727(2013). 100051 Given the potential to treat a wide array of diseases, there remains a need for novel modulators of toll like receptors, for example TLR-8. Potent and selective modulators of TLR-8 that have reduced potential for off target liabilities are particularly desireable. SUMMARY 100061 The present disclosure provides a compound of Formula (J): R4 NH A N NH2 R3 (0 or a pharmaceutically acceptable salt thereof, wherein: X is Nor CRI°; RI is selected from the group consisting of hydrogen, halogen, C14alkyl, CN, NRIRb —S(0)1-2R', and OR', wherein Ctalkyl is optionally substituted with 1 to 5 R2° groups; R2 is selected from the group consisting of hydrogen, halogen, C1.6alkyl, CN, — NR'Rb, —S(0)i.211' and OR', wherein Cialkyl is optionally substituted with 1 to 5 R2° groups; R3 is selected from the group consisting of hydrogen, halogen, C14alkyl, CN, — N12"Rb, —S(0)1.211', and OR', wherein CI-alkyl is optionally substituted with 1 to 5 R2° groups; R4 is C142 alkyl which is optionally substituted with 1 to 5 substituents independently selected from halogen, -OR', —NR'R b, CN, —C(0)R', — C(0)011', —C(0)NR'le, —0C(0)NR'Rb, —NRIC(0)Rb, —NR•C(0)NRb, — NrC(0)0Rb, —SR', —S(0)1.2R', —S(0)2NR•R b, —NR'S(0)2Rb, CI. 6haloalkyl, C34cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, C640 aryl, and 5 to 10 membered heteroaryl wherein 2 18435 the 5 to 10 membered heteroaryl has Ito 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein each C34cycloalkyl, 3 to 6 membered heterocyclyl, Cs-wary], and 5 to 10 membered heteroaryl is optionally substituted with 1 to 5 R 2' groups; RI° is selected from hydrogen, halogen, C14alkyl, CN, —NR'Rb, —S(0)1.2111, and OR*, wherein Cialkyl is optionally substituted with Ito 5 1t 2° groups each R2° is independently selected from the group consisting of halogen, CI. 6haloalkyl, CN, S(0)1.21V, and OR'; each R2' is independently selected from the group consisting of halogen, CI. 6alkyl, Ci4haloalkyl, CN, —NR'Rb, S(0)1.2r, and OR'; and each Rs and Rb are independently selected from the group consisting of hydrogen and CI4alkyl; wherein each CI.6alkyl is optionally substituted with Ito 5 substituents independently selected from halogen, hydroxyl, amino, 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and CI. 6haloalkyl; provided that when X is N, R' is Cl, R2 is H and R3 is H then R4 is not CH2CH20Me or CH2CH2S02Me. 100071 The present disclosure provides a compound of Formula (I): R4 NH or a pharmaceutically acceptable salt thereof, wherein: RI is selected from the group consisting of hydrogen, halogen, C14alkyl, CN, — NR*Rb, —S(0)1.21V, and OR', wherein C14alkyl is optionally substituted with Ito 5 R2° groups; R2 is selected from the group consisting of hydrogen, halogen, C14alkyl, CN, —S(0)1.2R1 and OR', wherein Chsalkyl is optionally substituted with Ito 5 R2° groups; 3 18435 R3 is selected from the group consisting of hydrogen, halogen, CI-alkyl, CN, — NR'Rb, —S(0)1-2R', and ORI, wherein CI-alkyl is optionally substituted with 1 to 5 R2° groups; it is C1-12 alkyl which is optionally substituted with Ito 5 substituents independently selected from halogen, -OR', CN, —C(0)111, — C(0)01V, —C(0)NR*Rb, —0C(0)NRIRb, —NIVC(0)Rb, —NR2C(0)NRb, — NRIC(0)01e, —SR', —S(0)1.2R', —S(0)2NR 1Rb, —NR'S(0)2Rb, CI. 6haloalkyl, C3_6cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, C6.10 aryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has Ito 3 heteroatoms selected from oxygen, nitrogen, and sulfur; wherein each C3.6cycloalkyl, 3 to 6 membered heterocyclyl, C6-10 aryl, and 5 to 10 membered heteroaryl is optionally substituted with Ito 5 R 2 ' groups; each R2° is independently selected from the group consisting of halogen, CI. shaloalkyl, CN, —NR'Rb, S(0)1.2R', and OR'; each R2 ' is independently selected from the group consisting of halogen, CI. 6alkyl, C1.6haloalkyl, CN, —NR'Rb, S(0)1.2W, and OR'; and each R' and Rb are independently selected from the group consisting of hydrogen and CI-alkyl; wherein each CI.alkyl is optionally substituted with 1 to 5 substituents independently selected from halogen, hydroxyl, amino, 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has 1 to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, and 6haloalkyl; provided that when R' is Cl, R2 is H and R3 is H then R's is not CH2CH20Me or CH2CH2S02Me. 10008/ The present disclosure provides a compound of Formula (IV): R13 R" YR12 HN R3 Formula (IV) ' 4 18435 wherein: IV is selected from the group consisting of hydrogen, halogen, CI.6 alkyl, CN, and OW, wherein C1.6 alkyl is optionally substituted with 1 to 5 R 2° groups; R2 is selected from the group consisting of hydrogen, halogen, Ci-is alkyl, CN, and OR', wherein C2.6 alkyl optionally substituted with 1 to 5 R 2° groups; 113 is selected from the group consisting of hydrogen, halogen, C14 alkyl, CN, and OR', wherein C1.6 alkyl is optionally substituted with I to 5 R 2° groups; R11 is selected from the group consisting of C1_2 alkyl, C3.6 cycloallcyl, and C13 haloalkyl; R12 is selected from C1.3 alkyl, halogen, -OR', CN, —C(0)IV, —C(0)01V, —C(0)NR'R1', —0C(0)NR'Rb, —NIVC(0)Rb, —NR'C(0)NRb, — NR1C(0)0Rb, —SR', —S(0)1-212,, —S(0)2NIVEtb, —NR'S(0)2Rb, C1.3 haloalkyl, C3-s cycloalkyl, 3 to 6 membered heterocyclyl wherein the 3 to 6 membered heterocyclyl has I to 3 heteroatoms selected from oxygen, nitrogen, and sulfur, Cs.maryl, and 5 to 10 membered heteroaryl wherein the 5 to 10 membered heteroaryl has Ito 3 heteroatoms selected from oxygen, nitrogen, and sulfur, wherein the CI.3 alkyl group is optionally substituted with 1 or 2 substituents independently selected from halogen, - OR', —NR'Rb, CN, —C(0)IV, —C(0)011', —C(0)NR'Rb, —0C(0)NRIRb, — NR1C(0)Rb, —NRIC(0)NRb, —NRIC(0)0Rb, —SR', —S(0)1.2124, — S(0)2NR'Rb, —NR'S(0)2Rb,
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