Compounds and compositions for the treatment of parasitic diseases

Abstract

Formula (Ia) [Formula 1] TIFF2022553261000408.tif44170 or a pharmaceutically acceptable salt thereof; methods for making the compounds of the invention, solid forms, pharmacologically active agent combinations, pharmaceutical compositions and methods of using such compounds and solid forms thereof to treat or prevent parasitic diseases, such as malaria, are provided herein.

Description

[Technical Field]

[0001] The present invention provides a class of compounds, pharmaceutical compositions containing such compounds and methods of using such compounds for treating or preventing parasitic diseases such as malaria. [Background technology]

[0002] Malaria is an infectious disease caused by four parasitic parasites: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria. These four parasites are typically transmitted through the bite of infected female Anopheles mosquitoes. Malaria is a problem in many parts of the world, and the burden of malaria has been steadily increasing over the past few decades. An estimated 1 to 3 million people die from malaria each year, the majority of whom are children under the age of five. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the most deadly malaria parasite, has developed resistance to nearly all available antimalarial drugs, except for artemisinin derivatives.

[0003] WO 2012 / 020215 and WO 2012 / 020217 disclose various aminoimidazolothiadiazoles for use as protein or lipid kinase inhibitors. However, the treatment of malaria requires targeted therapies that may be selective (i.e., capable of more selectively inhibiting a particular target molecule compared to other molecular targets, such as protein or lipid kinases, e.g., as described below), which may have the advantage of reducing side effects and may also be able to selectively treat malaria. Summary of the Invention [Problem to be solved by the invention]

[0004] In view of the above, there remains a need to develop new compounds as selective antiparasitic agents. The present invention provides such compounds, their pharmaceutically acceptable salts, their solid forms, their pharmaceutical compositions, and combinations thereof. The present invention further provides a method for treating, preventing, or ameliorating a parasitic disease, comprising administering to a subject in need thereof an effective amount of a compound of the present invention. [Means for solving the problem]

[0005] In one aspect, the present invention provides a compound of formula Ia: [ka] (In the formula, L is independently selected from NCH, O, and S; Z is N and CR 2 are each independently selected from Y 1 is C(R 3 )2;O,NR 3 and S; R 1 -C 1~4 Alkyl; Hydroxy-C 1~4 Alkyl-, alkoxy-C 1~4 Alkyl-, halo-C 1~4 Alkyl- and -X 1 -C 3~6 -cycloalkyl; R 2 -Hydrogen, -C 1~4 Alkyl, -C 1~4 Alkoxy, Halo-C 1~4 R is independently selected from alkyl, -halo, and a saturated 3- to 6-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from N, S, and O; 2 The carbocyclic or heterocyclic ring of 1~4 substituted with alkoxy; or R 1 and R2 is an atom through which R 1 and R 2 together with the atom to which it is attached, forms a saturated, unsaturated or partially unsaturated 3- to 6-membered heterocycle containing up to three heteroatoms selected from N, S and O; R 3 is hydrogen, C 1~4 Alkyl, amino, -X 1 -R 3a , -NH-X 1 -R 3a , hydroxy-substituted C 1~4 Alkyl; C 1~4 Alkoxy-substituted C 1~4 Alkyl; hydroxy, oxo, halo, -X 1 -CO2H, -X 1 -CO2NH2, -X 1 -SO2C 1~4 Alkyl, -X 1 -SO2N(C 1~4 alkyl)2, -X 1 -C 3~6 -cycloalkyl; R 3a is amino, -CO-C 1~4 Alkyl and N, NR 30 , S(O) 0~2 and O; R is independently selected from a 3- to 6-membered saturated, unsaturated, or partially unsaturated heterocycle containing up to three heteroatoms selected from 3a wherein the heterocycle is unsubstituted or substituted with one or two hydroxy or amino groups; or Any two R 3 is an atom through which R 3 N, NR along with the atom to which it is attached 4 , S(O) 0~2 and O form a saturated, unsaturated or partially unsaturated 3- to 6-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from; R 3 C 3~6 Cycloalkyl is unsubstituted or C 1~4 Alkyl, Amino, Amino-C 1~4 Alkyl, C 1~4Alkoxy, hydroxy, -X 1 CO2R 4a , -X 1 COR 4a , -X 1 C(O)NR 4a R 4b , -X 1 -cycloalkyl-R 4a 1 to 4 R independently selected from 4 is replaced by R 4a and R 4b is hydrogen, amino and amino-substituted C 1~4 are each independently selected from alkyl; X 1 is a bond and C 1~4 each independently selected from alkylene; n is independently selected from 0, 1, and 2; m is independently selected from 0, 1, 2, and 3; p is independently selected from 0, 1, 2, 3 and 4 or individual isomers and mixtures thereof, or pharmaceutically acceptable salts thereof.

[0006] In a second aspect, the present invention provides solid forms of the compound 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol and salts thereof.

[0007] In a third aspect, the present invention provides a pharmaceutical composition comprising a compound selected from formula Ia, its individual isomers and mixtures of isomers, or a pharmaceutically acceptable salt thereof, a solid form thereof mixed with one or more suitable excipients.

[0008] In a fourth aspect, the present invention provides a method of treating a disease in an animal wherein a compound of the invention is capable of preventing, inhibiting or ameliorating the pathology and / or symptoms of a disease caused by a parasite (e.g., Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malaria, Trypanosoma cruzi or a parasite of the Leishmania genus such as Leishmania donovani), the method comprising administering to the animal a therapeutically effective amount of a compound selected from Formula 1a, an individual isomer or mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

[0009] In a fifth aspect, the present invention provides the use of a compound selected from formula Ia, Ib, Ic, Id, Ie, If, Ig, Ih, Ii or Ij or a compound of the Examples in the manufacture of a medicament for treating a disease caused by a parasite in an animal. The disease may be malaria.

[0010] In a sixth aspect, the present invention provides a process for preparing a compound selected from Formula Ia, a prodrug derivative, an individual isomer or a mixture of isomers thereof, or a pharmaceutically acceptable salt thereof.

[0011] Other aspects of the present invention will become apparent from the following more detailed description of the invention and the claims. [Brief explanation of the drawings]

[0012] [Figure 1] 1 provides an X-ray diffraction pattern of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 2]FIG. 1 provides a differential scanning calorimetry (DSC) thermogram scan of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 3] 1 provides a TGA thermogram scan of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 4] FIG. 1 provides a scanning electron microscope (SEM) photograph of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 5] 1 provides an X-ray diffraction pattern of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 6] 1 provides a differential scanning calorimetry (DSC) thermogram scan of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 7] 1 provides a TGA thermogram scan of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. [Figure 8]1 provides a scanning electron microscope (SEM) photograph of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. DETAILED DESCRIPTION OF THE INVENTION

[0013] definition As used herein, "C 1~6 The term "alkyl" refers to a straight or branched hydrocarbon chain radical, consisting solely of carbon and hydrogen atoms, containing no unsaturation, and having from 1 to 6 carbon atoms attached to the remainder of the molecule by a single bond. 1~4 The term "alkyl" should be construed accordingly. 1~6 Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, n-pentyl, and 1,1-dimethylethyl (t-butyl).

[0014] As used herein, "C 1~6 The term "alkoxy" refers to a group of the formula -OR a where R a is a C as generally defined above. 1~6 It is an alkyl radical. C 1~6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, and hexoxy.

[0015] As used herein, "C 1~6 Alkoxy C 1~6 The term "alkyl" refers to a group of the formula -R a -OR a where each R a are independently C as defined above 1~6 The oxygen atom can be attached to any carbon atom of either alkyl radical. 1~6Alkoxy C 1~6 Examples of alkyl include, but are not limited to, methoxy-methyl, methoxy-ethyl, ethoxy-ethyl, 1-ethoxy-propyl, and 2-methoxy-butyl.

[0016] As used herein, "hydroxy C 1~6 The term "alkyl" refers to 1~6 C as defined above, where one of the hydrogen atoms of the alkyl radical is replaced by OH 1~6 Refers to alkyl radicals. Hydroxy C 1~6 Examples of alkyl include, but are not limited to, hydroxy-methyl, 2-hydroxy-ethyl, 2-hydroxy-propyl, 3-hydroxy-propyl, and 5-hydroxy-pentyl.

[0017] As used herein, "amino C 1~6 The term "alkyl" refers to 1~6 C as defined above, in which one of the alkyl group's hydrogen atoms is replaced by a primary amino group. 1~6 Refers to alkyl radicals. Amino C 1~6 Representative examples of alkyl include, but are not limited to, amino-methyl, 2-amino-ethyl, 2-amino-propyl, 3-amino-propyl, 3-amino-pentyl, and 5-amino-pentyl.

[0018] As used herein, "C 1~4 The term "alkylamino" refers to a group of the formula -NH-R a where R a is the C as defined above 1~4 It is an alkyl radical.

[0019] As used herein, "C 3~8 Cycloalkyl C 0~6 The term "alkyl" means a group consisting solely of carbon and hydrogen atoms, having from 3 to 8 carbon atoms, which is attached to the remainder of the molecule by a single bond or a C alkyl group as defined above. 1~6Refers to a stable monocyclic saturated hydrocarbon radical attached by an alkyl radical. 3~8 Cycloalkyl C 0~6 Examples of alkyl include, but are not limited to, cyclopropyl, cyclopropyl-methyl, cyclobutyl, cyclobutyl-ethyl, cyclopentyl, cyclopentyl-propyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0020] "Heterocycle", "heterocyclyl" or "heterocycloalkyl" means cycloalkyl, as defined in this Application, provided that one or more of the designated ring carbons is replaced by a moiety selected from -O-, -N=, -NR-, -C(O)-, -S-, -S(O)- or -S(O)-, where R is hydrogen, C 1~4 alkyl or nitrogen protecting group. For example, 3-8 membered heterocycloalkyl as used in this application to describe compounds of the invention includes morpholino, pyrrolidinyl, piperazinyl, piperidinyl, piperidinylone, 1,4-dioxa-8-aza-spiro[4.5]dec-8-yl, and the like.

[0021] "Halogen" refers to bromo, chloro, fluoro or iodo.

[0022] As used herein, "halogen C" 1~6 The term "alkyl" refers to a C alkyl group, as defined above, substituted with one or more halo radicals, as defined above. 1~6 Refers to alkyl radicals. Halogen C 1~6 Examples of alkyl include, but are not limited to, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,3-dibromopropan-2-yl, 3-bromo-2-fluoropropyl, and 1,4,4-trifluorobutan-2-yl.

[0023] As used herein, the term "heterocyclyl" or "heterocycle" refers to a stable 4-, 5-, 6-, or 7-membered non-aromatic monocyclic ring radical containing one, two, or three heteroatoms independently selected from nitrogen, oxygen, and sulfur. The heterocyclyl radical can be attached via a carbon atom or a heteroatom. Examples of heterocyclyls include, but are not limited to, azetidinyl, oxetanyl, pyrrolinyl, pyrrolidyl, tetrahydrofuryl, tetrahydrothienyl, piperidyl, piperazinyl, tetrahydropyranyl, morpholinyl, or perhydroazepinyl.

[0024] As used herein, "heterocyclyl C" 0~6 The term "alkyl" refers to a single bond or a C as defined above. 1~6 refers to a heterocycle, as defined above, attached to the rest of the molecule by an alkyl radical.

[0025] As used herein, the term "pharmaceutical composition" refers to a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a form suitable for oral or parenteral administration, together with at least one pharmaceutically acceptable carrier.

[0026] As used herein, the term "pharmaceutically acceptable carrier" refers to a substance useful in the preparation or use of a pharmaceutical composition, and would be known to those skilled in the art (see, for example, Remington The Science and Practice of Pharmacy, 22 nd Ed. Pharmaceutical Press, 2013, pp. 1049-1070) including suitable diluents, solvents, dispersion media, surfactants, antioxidants, preservatives, isotonicity agents, buffers, emulsifiers, absorption delaying agents, salts, drug stabilizers, binders, excipients, disintegrants, lubricants, wetting agents, sweeteners, flavoring agents, dyes, and combinations thereof.

[0027] As used herein, the term "subject" refers to primates (e.g., humans, male or female), dogs, rabbits, guinea pigs, pigs, rats, and mice. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

[0028] As used herein, the terms "inhibit," "inhibition," or "inhibiting" refer to the reduction or suppression of a given condition, symptom, or disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0029] As used herein, the terms "treat," "treating," or "treatment" of any disease or disorder refer to the alleviation or amelioration of the disease or disorder (i.e., slowing or arresting the progression of the disease or at least one of its clinical symptoms); or the alleviation or amelioration of at least one physical parameter or biomarker associated with the disease or disorder, including those that may not be discernible by the patient.

[0030] As used herein, the terms "prevent," "preventing," or "prevention" of any disease or disorder refers to prophylactic treatment of the disease or disorder or delaying the onset or progression of the disease or disorder.

[0031] As used herein, a subject is "in need of" a treatment if such subject would derive biological, medical, or quality of life benefit from such treatment.

[0032] As used herein, the terms "a," "an," "the," and similar terms used in connection with the present invention (particularly in the claims) are to be construed to encompass both the singular and the plural unless otherwise indicated herein or clearly contradicted by context.

[0033] All methods described herein can be performed in any suitable order unless otherwise indicated herein or clearly contradicted by context. The use of any examples or exemplary language (e.g., "etc.") provided herein is intended merely to further clarify the invention and does not otherwise limit the scope of the claimed invention.

[0034] The present invention provides a novel class of compounds, pharmaceutical compositions containing such compounds, and methods of using such compounds for treating or preventing parasite-related diseases or disorders. In particular, the compounds can be used to treat malaria.

[0035] In one embodiment, a compound of formula Ia: [ka] For the compound L is independently selected from NCH, O, and S; Z is N and CR 2 are each independently selected from Y 1 is C(R 3 )2;O,NR 3 and S; R 1 -C 1~4 Alkyl; Hydroxy-C 1~4 Alkyl-, alkoxy-C 1~4 Alkyl-, halo-C 1~4 Alkyl- and -X 1 -C 3~6 -cycloalkyl; R 2 -Hydrogen, -C 1~4 Alkyl, -C 1~4 Alkoxy, Halo-C 1~4 R is independently selected from alkyl, -halo, and a saturated 3- to 6-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from N, S, and O; 2The carbocyclic or heterocyclic ring of 1~4 substituted with alkoxy; or R 1 and R 2 is an atom through which R 1 and R 2 together with the atom to which it is attached, forms a saturated, unsaturated or partially unsaturated 3- to 6-membered heterocycle containing up to three heteroatoms selected from N, S and O; R 3 is hydrogen, C 1~4 Alkyl, amino, -X 1 -R 3a , -NH-X 1 -R 3a , hydroxy-substituted C 1~4 Alkyl; C 1~4 Alkoxy-substituted C 1~4 Alkyl; hydroxy, oxo, halo, -X 1 -CO2H, -X 1 -CO2NH2, -X 1 -SO2C 1~4 Alkyl, -X 1 -SO2N(C 1~4 alkyl)2, -X 1 -C 3~6 -cycloalkyl; R 3a is amino, -CO-C 1~4 Alkyl and N, NR 30 , S(O) 0~2 and O; R is independently selected from a 3- to 6-membered saturated, unsaturated, or partially unsaturated heterocycle containing up to three heteroatoms selected from 3a wherein the heterocycle is unsubstituted or substituted with one or two hydroxy or amino groups; or Any two R 3 is an atom through which R 3 N, NR along with the atom to which it is attached 4 , S(O) 0~2 and O form a saturated, unsaturated or partially unsaturated 3- to 6-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from; R 3 C3~6 Cycloalkyl is unsubstituted or C 1~4 Alkyl, Amino, Amino-C 1~4 Alkyl, C 1~4 Alkoxy, hydroxy, -X 1 CO2R 4a , -X 1 COR 4a , -X 1 C(O)NR 4a R 4b , -X 1 -cycloalkyl-R 4a 1 to 4 R independently selected from 4 is replaced by R 4a and R 4b is hydrogen, amino and amino-substituted C 1~4 are each independently selected from alkyl; X 1 is a bond and C 1~4 each independently selected from alkylene; n is independently selected from 0, 1, and 2; m is independently selected from 0, 1, 2, and 3; p is independently selected from 0, 1, 2, 3, and 4; or and pharmaceutically acceptable salts thereof.

[0036] In another embodiment, the compound has formula Ib: [ka] (In the formula, R 2a and R 2b -Hydrogen, -C 1~4 Alkyl, -C 1~4 Alkoxy, Halo-C 1~4 R is independently selected from alkyl, -halo, and a saturated 3- to 6-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from N, S, and O; 2 The carbocyclic or heterocyclic ring of 1~4 substituted with alkoxy) It has.

[0037] In another embodiment, L is O. In another embodiment, L is NCH3. In another embodiment, L is S.

[0038] In another embodiment, Z is N. In another embodiment, Z is CR 2 is.

[0039] In another embodiment, Y 1 is C(R 3 )2. In another embodiment, Y 1 is O. In another embodiment, Y 1 is NR 3 In another embodiment, Y 1 is S.

[0040] In another embodiment, R 1 Ha-C 1~4 In another embodiment, R 1 is hydroxy-C 1~4 In another embodiment, R 1 is alkoxy-C 1~4 In another embodiment, R 1 Halo-C 1~4 In another embodiment, R 1 -X 1 -C 3~6 -cycloalkyl.

[0041] In another embodiment, R 2 is -hydrogen. In another embodiment, R 2 Ha-C 1~4 In another embodiment, R 2 is C 1~4 In another embodiment, R 2 Halo-C 1~4 In another embodiment, R 2 is -halo. In another embodiment, R 2is a saturated 3- to 6-membered carbocyclic ring. 2 is a heterocycle containing up to three heteroatoms selected from N, S, and O. In another embodiment, R 2 is a carbocyclic ring or R 2 In another embodiment, the heterocycle of R 2 is one or two C 1~4 It is substituted with alkoxy.

[0042] In another embodiment, R 1 and R 2 is an atom through which R 1 and R 2 together with the atom to which it is attached, forms a saturated, unsaturated or partially unsaturated 3- to 6-membered heterocycle containing up to three heteroatoms selected from N, S and O.

[0043] In another embodiment, X 1 is a bond. In another embodiment, X 1 is C 1~4 It is alkylene.

[0044] In another embodiment, n is 0. In another embodiment, n is 1. In another embodiment, n is 2.

[0045] In another embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3.

[0046] In another embodiment, p is 0. In another embodiment, p is 1. In another embodiment, p is 2. In another embodiment, p is 3. In another embodiment, p is 4.

[0047] In another embodiment, the compound has formula Ic: [ka] (In the formula, R3b , R 3c , R 3e and R 3e is hydrogen, C 1~4 Alkyl, amino, -X 1 -R 3a , -NH-X 1 -R 3a , hydroxy-substituted C 1~4 Alkyl; C 1~4 Alkoxy-substituted C 1~4 Alkyl; hydroxy, oxo, halo, -X 1 -CO2H, -X 1 -CO2NH2, -X 1 -SO2C 1~4 Alkyl, -X 1 -SO2N(C 1~4 alkyl)2 and -X 1 -C 3~6 -cycloalkyl) It has.

[0048] In another embodiment, the compound has formula Id: [ka] (In the formula, R 3b , R 3c , R 3e and R 3e is hydrogen, C 1~4 Alkyl, amino, -X 1 -R 3a , -NH-X 1 -R 3a , hydroxy-substituted C 1~4 Alkyl; C 1~4 Alkoxy-substituted C 1~4 Alkyl; hydroxy, oxo, halo, -X 1 -CO2H, -X 1 -CO2NH2, -X 1 -SO2C 1~4 Alkyl, -X 1 -SO2N(C 1~4 alkyl)2 and -X 1 -C 3~6 -cycloalkyl) It has.

[0049] In another embodiment, the compound has formula Ie: [ka] (In the formula, R 3b and R 3c is hydrogen, C 1~4 Alkyl, amino, -X 1 -R 3a , -NH-X 1 -R 3a , hydroxy-substituted C 1~4 Alkyl; C 1~4 Alkoxy-substituted C 1~4 Alkyl; hydroxy, oxo, halo, -X 1 -CO2H, -X 1 -CO2NH2, -X 1 -SO2C 1~4 Alkyl, -X 1 -SO2N(C 1~4 alkyl)2 and -X 1 -C 3~6 -cycloalkyl) It has.

[0050] In another embodiment, the compound has the formula If: [ka] (In the formula, Y 2 is C(R 4 )2;O,NR 4 and S; Y 3 is C(R 4 )2;O,NR 4 and S; (Dashed lines indicate that the bond is a single or double bond.) It has.

[0051] In another embodiment, the compound has formula Ig: [ka] (In the formula, Y 4 is C(R 4 )2;O,NR 4 and S, each independently selected from It has.

[0052] In another embodiment, the compound has formula Ih: [ka] (In the formula, Y 5 is C(R 4 )2;O,NR 4 and S; Y 6 is C(R 4 )2;O,NR 4 and S, each independently selected from It has.

[0053] In another embodiment, m is 0. In another embodiment, m is 1. In another embodiment, m is 2. In another embodiment, m is 3.

[0054] In another embodiment, the compound has formula Ii: [ka] (In the formula, Y 7 is C(R 4 )2;O,NR 4 and S; Y 8 is C(R 4 )2;O,NR 4 and S, each independently selected from It has.

[0055] In another embodiment, the compound has formula Ij: [ka] (In the formula, Y 9 is C(R 4 )2;O,NR 4 and S; Y 10 is C(R 4 )2;O,NR 4 and S, each independently selected from It has.

[0056] In another embodiment, Y 1 is C(OH)CH2NH2.

[0057] In another embodiment, R 3 is hydrogen. In another embodiment, R 3 is C 1~4 In another embodiment, R 3 is amino. In another embodiment, R 3 -X 1 -R 3a In another embodiment, R 3 Ha-NH-X 1 -R 3a In another embodiment, R 3 is hydroxy-substituted C 1~4 In another embodiment, R 3 is C 1~4 Alkoxy-substituted C 1~4 In another embodiment, R 3 is hydroxy. In another embodiment, R 3 is oxo. In another embodiment, R 3 is halo. In another embodiment, R 3 -X 1 In another embodiment, R 3 -X 1 In another embodiment, R 3 -X1 -SO2C 1~4 In another embodiment, R 3 -X 1 -SO2N(C 1~4 In another embodiment, R 3 -X 1 -C 3~6 -cycloalkyl.

[0058] In another embodiment, any two R 3 is an atom through which R 3 N, NR along with the atom to which it is attached 4 , S(O) 0~2 and O to form a saturated, unsaturated, or partially unsaturated 3- to 6-membered carbocyclic or heterocyclic ring containing up to three heteroatoms selected from: 3 C 3~6 The cycloalkyl is unsubstituted. In another embodiment, R 3 C 3~6 Cycloalkyl is C 1~4 Alkyl, Amino, Amino-C 1~4 Alkyl, C 1~4 Alkoxy, hydroxy, -X 1 CO2R 4a , -X 1 COR 4a , -X 1 C(O)NR 4a R 4b and -X 1 -cycloalkyl-R 4a 1 to 4 R independently selected from 4 is replaced by .

[0059] In another embodiment, R 3a is amino. In another embodiment, R 3a Ha-CO-C 1~4 In another embodiment, R 3a is N, NR 30 , S(O) 0~2 and O. In another embodiment, R3a In another embodiment, the heterocycle of R 3a The heterocycle of is substituted with one or two hydroxy or amino groups.

[0060] In another embodiment, R 4a is hydrogen. In another embodiment, R 4a is amino. In another embodiment, R 4a is amino-substituted C 1~4 In another embodiment, R 4b is hydrogen. In another embodiment, R 4b is amino. In another embodiment, R 4b is amino-substituted C 1~4 It is alkyl.

[0061] In further embodiments, the compounds are Examples 4-0 to 58-2: 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 3-(aminomethyl)-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; (4-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol). (4-amino-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; (3S,5S)-5-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol; 3-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)a Zetidin-3-ol;4-(aminomethyl)-1-(5-(5-chloro-4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(2-ethoxy-5-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-2,8-diazaspiro[3.5 ]nonane;8-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine;4-(aminomethyl)-1-(5-(5-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;9-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-4,9-diazaspiro[5.5]undecane;4-(Aminomethyl)-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(Aminomethyl)-1-(5-(3-chloro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(Aminomethyl)-1-(5-(4-cyclopropyl-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (3S,4R) -4-Amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol;(3R,4S)-4-Amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol;4-(Aminomethyl)-1-(5-(3,5-difluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)- 1-(5-(2,3-Dihydrobenzofuran-7-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(aminomethyl)-1-(5-(2-methoxy-3-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (R)-1-(1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)cyclopropan-1-amine; (4-((Cyclo 4-(aminomethyl)-1-(5-(2-methoxy-3-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(aminomethyl)-1-(5-(2-methoxy-3-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 2-(4-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-2-yl)ethan-1-ol;3-(Aminomethyl)-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)azetidin-3-ol;(3S,4R)-3-Fluoro-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-amine;(3R,4S)-3-Fluoro-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-amine;(3S,4R)-4 -amino-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; (4-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-2-yl)methanol; 8-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 8-(5-(4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8-azaspiro[4.5]decan-3-amine; 4-(aminomethyl)-1-(5-(2-ethoxy-4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 3-(aminomethyl)-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol 4-(aminomethyl)-1-(5-(4-chloro-2-(2-methoxyethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (S)-3-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; (R)-3-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol;4-(Aminomethyl)-1-(5-(4-fluoro-2-(trifluoromethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)-1-(5-(3-fluoro-2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)-1-(5-(2-(cyclopropylmethoxy)-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-ol Lysin-4-ol;4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(4-fluoro-5-isopropyl-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;8-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8-azaspipri 4-(Aminomethyl)-1-(5-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 2-(5-(4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-azaspiro [3.3]Heptan-5-amine; (4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(aminomethyl)-1-(5-(2-ethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(aminomethyl)-1-(5-(2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(S)-(3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)methanol; (R)-(3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)methanol; (3R,5R)-5-fluoro-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine 3-Amine;(3R,4R)-4-Amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol;(3S,4S)-4-Amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol;1-(5-(2-Methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-methylpyrrolidin-3-amine;1- (5-(2-Methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-methylpyrrolidin-3-amine; 1-(5-(6-Isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-3-methylpyrrolidin-3-amine; 2-((1-(5-(6-Isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)amino)ethane-1- ol;4-(aminomethyl)-1-(5-(2-methoxy-4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol;4-(aminomethyl)-1-(5-(3,4-difluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(3S,4R)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; (3S,4R)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; 4-(aminomethyl)-1-(5-(4; -chloro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(aminomethyl)-1-(5-(4,5-difluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (R)-(3-amino-1-(5-(2-ethoxy-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)methanol; (S)-(3-amino-1-(5-(2-ethoxy-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)methanol; (3S,4R)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)methanol;4-(aminomethyl)-1-(5-(2-methoxy-4,5-dimethylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(3S,4R)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(3R,4S)-3-amino-1-(5- (4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;2-(4-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperazin-1-yl)ethan-1-ol;3-(Aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol;4-(Aminomethyl) -1-(5-(2-methoxy-4-(tetrahydro-2H-pyran-4-yl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(2-(4-(aminomethyl)-4-hydroxypiperidin-1-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl)-3-methoxybenzonitrile; 4-(aminomethyl)-1-(5-(2,6-dimethoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(4-Amino-1-(5-(4-chloro-2-(2-methoxyethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 3-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)azetidin-3-ol; 4-(aminomethyl)-1-(5-(2-ethoxy-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(amino Methyl)-1-(5-(6-isopropyl-2-(2-methoxyethoxy)pyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)-1-(5-(3-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)-1-(5-(3-methoxynaphthalen-2-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(3S,4S) -3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(3R,4R)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(4aR,8aR)-6-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-2H-pyrido[4,3-b][1,4]oxazolidin-4-ol;(4aR,8aR)-6-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-2H-pyrido[4,3-b][1,4]oxazolidin-4-ol 1'-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-[1,3'-biazetidin]-3-ol; (4-amino-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(aminomethyl)-1-(5-(5-chloro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)-1-(5-(2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(Aminomethyl)-1-(5-(4-fluoro-2-isopropoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)morpholine;4-(Aminomethyl)-1- (5-(2-(trifluoromethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 3-(aminomethyl)-1-(5-(2-ethoxy-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; 1-(1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)azetidin-3-ol; 4-(aminomethyl)-1-(5- (2-Methoxy-6-(trifluoromethyl)pyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (4-(aminomethyl)-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)thiomorpholine 1,1-dioxy (4-amino-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; (4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(aminomethyl)-1-(5-(4-fluoro-2-methoxy-5-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(4-Amino-1-(5-(2-ethoxy-4-fluorophenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(Aminomethyl)-1-(5-(2,4-dimethoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; N-((3aR,7aR)-2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-3aH-pyrrolo [3,4-c]pyridin-3a-yl)acetamide;2-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-2,7-diazaspiro[3.4]oct-6-en-6-amine;8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-3,8-diazaspiro[4.5]dec-2-en-2 ... [2,1-b][1,3,4]thiadiazol-2-yl)-3-oxa-1,8-diazaspiro[4.5]dec-1-en-2-amine; 8-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-3,8-diazaspiro[4.5]dec-2-en-2-amine; (3aS,5S,6S,7aR)-6-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)- (3aS,5S,6S,7aR)-6-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol; (3aS,5S,6S,7aR)-6-amino-2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol;(9-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9-azaspiro[5.5]undecan-3-yl)methanamine; (3-amino-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)azetidin-3-yl)methanol; (3-fluoro-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine (3S,4S)-8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8-azaspiro[4.5]decan-2-yl)methanamine;2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-2-azaspiro[3.4]octan-7-amine;(3S,4S)-8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-oxa-8-azaspiro[4.5]decan-2-yl)methanamine 4-(aminomethyl)-1-(5-(2-(dimethylamino)-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(6-methyl-2-(methylthio)pyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;3-(aminomethyl)-1-(5-(4-fluoro-2- 8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine; 3-amino-1-(9-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4,9-triazaspiro[5.5]undecan-4-yl)-3-methylbutan-1-one;5-(6-Isopropyl-2-methoxypyridin-3-yl)-2-(1,4,9-triazaspiro[5.5]undecan-9-yl)imidazo[2,1-b][1,3,4]thiadiazole; 5-(4-Fluoro-2-methoxyphenyl)-2-(1,4,9-triazaspiro[5.5]undecan-9-yl)imidazo[2,1-b][1,3,4]thiadiazole; 1-(5-(4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-(morpholinomethyl)piperidin-4-amine; 7-(5-(4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine;(1-(5-(4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-((oxetan-3-ylmethyl)amino)piperidin-4-yl)methanol;(1-(5-(4-Fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)- 4-((2-Morpholinoethyl)amino)piperidin-4-yl)methanol;4-((3-aminopropyl)amino)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol;6-(aminomethyl)-2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-azaspiro[3.3]heptan-6-ol;(S)-3-(aminomethyl)-1-(5-(6-isopropyl)amino)- (R)-3-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol;(S)-3-(aminomethyl)-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol;(R ...S)-3-(aminomethyl)-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol;(R)-3-(aminomethyl)-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol (3S,4S)-4-amino-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol; 3-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol; (3S,4S)-4-amino-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol;(3R,4R)-4-amino-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol; (3R,4R)-4-amino-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol; (3S,4S)-4-amino-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol (3R,4R)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol; (3S,4S)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol; (3R,4R)-4-amino-1-(5-(2-methoxy-6-methylpyridine-3 (3S,4S)-4-amino-1-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol;(3S,4S)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol;(3R,4R)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol;(3R,4R)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol No-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol;(3R,4R)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol;4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide;N-((1-aminocyclopropyl)methyl)-4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide;N-(2-amino-2-methylpropyl)-8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-thia-8-azaspiro[4.5]decane-4-carboxamide 1,1-dioxide;2-(4-amino-1-(5-(4-fluoro) 2-(4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)propan-2-ol;4-(aminomethyl)-1-(5-(4-(1-hydroxycyclobutyl)-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)propan-2-ol;2-(4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)propan-2-ol;4-(aminomethyl)-1-(5-(4-(1-hydroxycyclobutyl)-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol ;((1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-((methylsulfonyl)methyl)piperidin-4-yl)methanamine;1-(4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)-N,N-dimethylmethanesulfonamide;((3R,5S)-5-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2, 1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol;(4S,4aR,7aS)-6-(5-(2-ethoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;(4S,4aR,7aS)-6-(5-(2-methoxy-4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;(4R,4aS,7aR)-6-(5-(2-methoxy-4-(trifluoromethyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine; (4S,4aR,7aS)-6-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine; (4R,4aS,7aR)-6-(5-(6 -isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;(4S,4aR,7aS)-6-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;(4R,4aS,7aR)-6-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b ][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;((4S,4aS,7aR)-6-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;(4S,4aS,7aR)-6-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine (4R,4aR,7aS)-6-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine; (4S,4aR,7aR)-6-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine;(3aS,5R,7R,7aR)-7-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol; (3aR,4S,5S,7aS)-4-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol; (3aR,4S,5R,7aS)-4-amino-2-(5-(2- (3aR,4S,5R,7aS)-4-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol; (3aR,4S,5R,7aS)-4-amino-2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4] (3aR,4R,7aS)-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-amine;4-(aminomethyl)-1-(5-(4-chloro-5-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1 -(5-(2-isopropoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(aminomethyl)-1-(5-(2-ethoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (4-amino-1-(5-(2-ethoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol;3-(Aminomethyl)-1-(5-(2-ethoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)azetidin-3-ol; (4-Amino-1-(5-(4-(1,2-difluoroethyl)-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(Aminomethyl)-1-(5-(2-(2-hydroxyethoxy)-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (4-Amino-1-(5-(4-(1,2-difluoroethyl)-2-methoxyphenyl)imidazo[2,1-b]; [1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol;4-(aminomethyl)-1-(5-(4-(1,2-difluoroethyl)-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(2-(2,2-difluoroethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(4-isopropyl-2-methoxy ... 4-(aminomethyl)-1-(5-(2-ethoxy-4-isopropylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(2-methoxy-4-(tetrahydrofuran-3-yl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(2-methoxy-4-(tetrahydrofuran-3-yl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-(aminomethyl)-1-(5-(2-methoxy-4-isopropylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol 4-(aminomethyl)-1-(5-(2-methoxy-4-(1-methoxycyclobutyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(4-amino-1-(5-(2-(2-fluoroethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol;4-(aminomethyl)-1-(5-(2-methoxy-4-(1-methoxycyclobutyl)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (4-amino-1-(5-(2-(2,2-difluoroethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; (4-amino-1-(5-(2-(2,2-difluoroethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(aminomethyl)-1-(5-(2-(2,2-difluoroethoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;(4-amino-1-(5-(2-(2,3-difluoropropoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol; 4-(aminomethyl)-1-(5-(2-(2,3-difluoropropoxy)phenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol; 4-(aminomethyl)-1-(5-(4-chloro-5-isopropyl) -2-Methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol;4-Amino-8-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-thia-8-azaspiro[4.5]decane 1,1-dioxide;1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thia 2-(3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-yl)propan-2-ol;3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol (3R,4R,5S)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidine-3,5-diol; and ((3S,4S)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-yl)methanol.

[0062] Crystalline form of Compound I In one aspect, the present invention relates to crystalline form K' of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I), having an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 5.3, 12.3, and 22.5±0.2 degrees 2θ. In some embodiments, crystalline form K' of Compound I is characterized by an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 5.3, 10.6, 12.3, 21.2, 22.5, and 23.0±0.2 degrees 2θ. In some embodiments, crystalline form K' is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 2θ values ​​selected from 5.3, 10.6, 12.3, 17.0, 17.3, 19.4, 20.3, 21.2, 22.5, 23.0, 24.8, 27.1, 32.0±0.2 degrees 2θ. In some embodiments, the present invention relates to a method for preparing crystalline form K' of compound I, comprising evaporating a solution of compound I in about 1:1 (v / v) n-butanol / dichloromethane to crystallize compound I as crystalline form K'.

[0063] In one embodiment, crystalline form K' of Compound I is provided in substantially pure form. This crystalline form K' of Compound I in substantially pure form can be used in pharmaceutical compositions, such as the ophthalmic formulations described herein. In some embodiments, the disclosure provides pharmaceutical formulations comprising crystalline form K' of Compound I. In some embodiments, the disclosure provides ophthalmic suspensions of Compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of Compound I is present as crystalline form K'.

[0064] In one aspect, the present invention relates to crystalline form M of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I), having an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 11.1, 18.5, and 19.1±0.2 degrees 2θ. In certain embodiments, crystalline form M of Compound I is characterized by an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 11.1, 12.1, 18.5, 19.1, 20.1, and 21.4±0.2 degrees 2θ. In some embodiments, crystalline form M is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 2θ values ​​selected from 11.1, 12.1, 18.5, 19.1, 20.1, 21.4, 21.7, 22.2, 23.1, 26.4, 273, and 29.7±0.2 degrees 2θ. In some embodiments, the present invention relates to a method for preparing crystalline form M of compound I, comprising slurrying crystalline form B of compound I in acetone at room temperature for at least 24 hours, at least 2 days, at least 3 days, at least 4 days, or at least 5 days. Alternatively, crystalline form M can be obtained by slurrying crystalline form B of compound I in acetone, ethanol, 1:1 ethanol / water, methanol, or 1:1 methanol / water at 50° C. for 2 weeks.

[0065] In one embodiment, crystalline form M of Compound I is provided in substantially pure form. This crystalline form M of Compound I in substantially pure form can be used in pharmaceutical compositions, such as the ophthalmic formulations described herein. In some embodiments, the disclosure provides pharmaceutical formulations comprising Compound I in crystalline form M. In some embodiments, the disclosure provides ophthalmic suspensions of Compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of Compound I is present as crystalline form M.

[0066] In one aspect, the present invention provides a crystalline hydrate H of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I) having an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 6.6, 12.2, and 15.8±0.2° 2θ. B In certain embodiments, the crystalline hydrate HB of Compound I is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from: 6.6, 12.2, 14.6, 15.8, 16.1, 18.5, 20.9, 24.7±0.2° 2θ. In some embodiments, the crystalline hydrate HB of Compound I is characterized by an X-ray diffraction pattern having three or more peaks at 2θ values ​​selected from: 6.6, 12.2, 14.6, 15.8, 16.1, 18.5, 20.9, 24.7±0.2° 2θ. B is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 2θ values ​​selected from 6.6, 11.7, 12.2, 14.6, 15.8, 16.1, 18.5, 19.7, 20.9, 24.7, 26.5, 27.7, 29.3±0.2 degrees 2θ. In some embodiments, the present invention provides a method for preparing crystalline form B of Compound I by slurrying the crystalline form B of Compound I in about a 1:1 mixture of acetone and water at room temperature for at least 5 days, at least 6 days, or at least 7 days to obtain crystalline hydrate H B 2. A crystalline hydrate of Compound I, comprising providing the crystalline hydrate H B The present invention relates to a method for preparing

[0067] In one embodiment, hydrate H of Compound I B is provided in substantially pure form. This hydrate H of Compound I in substantially pure form B may be used in pharmaceutical compositions, such as the ophthalmic formulations described herein. In some embodiments, the present disclosure provides methods for preparing Compound I as the hydrate H B In some embodiments, the present disclosure provides an ophthalmic suspension of Compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of Compound I is present as the hydrate H B It exists as.

[0068] In one aspect, the present invention relates to crystalline form Q of 4-(7-hydroxy-2-isopropyl-4-oxo-4H-quinazolin-3-yl)-benzonitrile (Compound I), having an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 11.2, 12.2, 19.1±0.2 degrees 2θ. In certain embodiments, crystalline form Q of Compound I is characterized by an X-ray diffraction pattern with three or more peaks at 2θ values ​​selected from 11.2, 12.2, 18.5, 19.1, 20.1, 22.0, 22.5, 23.3, 26.5±0.2 degrees 2θ. In some embodiments, crystalline form A is characterized by an X-ray diffraction pattern having 3 or more, 4 or more, 5 or more, 6 or more, or 7 or more peaks at 2θ values ​​selected from 11.2, 12.2, 17.7, 18.5, 19.1, 20.1, 22.0, 22.5, 23.3, 24.2, 24.6, 26.5, 28.5±0.2 degrees 2θ. In some embodiments, the present invention relates to a method for preparing crystalline form Q of compound I according to claims 10-11, comprising slurrying crystalline form B of compound I with about 1:1 (v / v) n-butanol / dichloromethane to obtain compound I as crystalline form Q.

[0069] In one embodiment, crystalline form Q of Compound I is provided in substantially pure form. This crystalline form Q of Compound I in substantially pure form can be used in pharmaceutical compositions, such as the ophthalmic formulations described herein. In some embodiments, the disclosure provides pharmaceutical formulations comprising Compound I in crystalline form Q. In some embodiments, the disclosure provides ophthalmic suspensions of Compound I, wherein at least 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least 90% of Compound I is present as crystalline form Q.

[0070] A further embodiment of the invention is a method for treating a Plasmodium associated disease in a subject to prevent, inhibit or ameliorate the pathology and / or symptoms of the Plasmodium associated disease, comprising administering to the subject in vivo or in vitro a therapeutically effective amount of a compound of the invention, alone or in combination with a second agent.

[0071] A further embodiment is a method for treating a Plasmodium-associated disease in a subject to prevent, inhibit, or ameliorate the pathology and / or symptoms of the Plasmodium-associated disease, comprising administering to the subject in vivo or in vitro a therapeutically effective amount of a compound of any embodiment described herein, alone or in combination with a second agent.

[0072] In a further embodiment, the Plasmodium associated disease is malaria.

[0073] In further embodiments, the second agent is selected from a kinase inhibitor, an antimalarial agent, and an anti-inflammatory agent. The antimalarial agent is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amopiroquine, sulfonamides, artemisinin, artefren, artemether, artesunate, primaquine, pyronaridine, KAE-609, and KAF-156.

[0074] In further embodiments, the compound of the invention may be administered before, simultaneously with, or after the second agent.

[0075] In a further embodiment, the subject is a human.

[0076] Pharmacology and Usefulness The compounds of the invention are useful for the treatment and / or prevention of infections such as those caused by Plasmodium falciparum; Plasmodium vivax; Plasmodium ovale; and Plasmodium malaria; Trypanosoma cruzi and parasites of the Leishmania genus, such as Leishmania donovani.

[0077] Malaria is an infectious disease caused by four parasitic parasites: Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, and Plasmodium malaria. These four parasites are typically transmitted through the bite of infected female Anopheles mosquitoes. Malaria is a problem in many parts of the world, and the burden of malaria has been steadily increasing over the past few decades. An estimated 1 to 3 million people die from malaria each year, the majority of whom are children under the age of five. This increase in malaria mortality is due in part to the fact that Plasmodium falciparum, the most deadly malaria parasite, has developed resistance to nearly all available antimalarial drugs, except for artemisinin derivatives.

[0078] The phylum Apicomplexa contains many members that are pathogens of humans or animals, including, but not limited to, Plasmodium spp. (Malaria), Toxoplasma gondii (human congenital neurological defects), Eimeria spp. (pathogens of poultry and cattle), Cryptosporidia (opportunistic human and animal pathogens), Babesia (bovine parasites), and Theileria (bovine parasites). Pathogenesis associated with these parasitic diseases relies on repeated cycles of host cell invasion, intracellular replication, and host cell lysis. Therefore, understanding parasite proliferation is essential for the development of new drugs and vaccines to treat malaria, for example.

[0079] In vertebrate hosts, the parasite undergoes two major developmental stages, the hepatocellular and the erythrocytic, but it is the erythrocytic stage of its life cycle that causes severe pathology. During the erythrocytic stage, the parasite undergoes a complex but well-synchronized series of stages, suggesting the existence of tightly regulated signaling pathways.

[0080] Calcium functions as an intracellular messenger to control the synchronization and development of red blood cell life phases. Plasmodium spp. genomes reveal numerous sequence identities with calcium-binding / sensing protein motifs, including Pf39, calmodulin, and calcium-dependent protein kinase (CDPK). Plasmodium CDPKs, Plasmodium CDPK3 and 4, have been shown to be involved in mosquito infection. CDPK4 has been demonstrated to be essential for sexual reproduction in the mosquito midgut by transducing calcium signals into cellular responses and regulating cell cycle progression of male gametocytes. CDPK3 regulates ookinete gliding motility and penetration of the midgut epithelium. P. falciparum CDPK1 (PfCDPK1) is expressed in the late schizogonial blood stage and the infective sporozoite stage and is secreted into the parasitophorous vacuole by an acylation-dependent mechanism. It can be myristoylated and is abundant in detergent-resistant membrane fractions isolated from schizogonial parasites. Ontology-based pattern discrimination analysis reveals that PfCDPK1 is clustered with genes associated with either parasite escape or erythrocyte invasion. Direct inhibition of PfCDPK1 can halt progression of the erythrocyte life cycle in late schizogonial parasites.

[0081] Therefore, kinase activity is distributed throughout all stages of P. falciparum parasite maturation, and the kinase inhibitors of the present invention can be used to treat Plasmodium-related diseases. In particular, the kinase inhibitors of the present invention can be a pathway for treating malaria by inhibiting the kinase PfCDPK1. The following in vitro cell assay can be used to evaluate the activity of the compounds of the present invention against various malaria parasite strains.

[0082] The compounds of the present invention are relatively inactive against certain protein kinases, such as receptor tyrosine protein kinase or fetal liver kinase-2 (FLT3), phosphatidylinositol 3-kinase (PIK3CA), proto-oncogene, serine / threonine kinase (PIM1), mitogen-activated protein kinase-activated protein kinase 2 (MapKap2 or MK-2); and cannabinoid receptor 1 (CB1).

[0083] In accordance with the foregoing, the present invention further provides a method for preventing or treating malaria in a subject in need of such treatment, comprising administering to said subject a therapeutically effective amount of a compound selected from Formulae Ia to Ij, a compound of the Examples, or a pharmaceutically acceptable salt thereof. The required dosage will vary depending on the form of administration, the particular condition being treated, and the effect desired.

[0084] Administration and Pharmaceutical Compositions In general, the compounds of the present invention are administered in a therapeutically effective amount, either alone or in combination with one or more therapeutic agents, by any of the conventional and accepted methods known in the art. Therapeutically effective amounts can vary widely depending on the severity of the disease, the age and relative health of the subject, the potency of the compound used, and other factors. In general, satisfactory results have been shown to be obtained systemically at a daily dosage of about 0.03 to 2.5 mg / kg of body weight. Indicated daily dosages for larger mammals, such as humans, range from about 0.5 mg to about 100 mg, conveniently administered, for example, in divided doses up to four times daily or in delayed form. Suitable unit dosage forms for oral administration contain about 1 to 50 mg of active ingredient.

[0085] The compounds of the present invention can be administered as pharmaceutical compositions by any conventional route, in particular enterally, for example orally, for example in the form of tablets or capsules, or parenterally, for example in the form of injectable solutions or suspensions, topically, for example in the form of lotions, gels, ointments or creams, or intranasally or in the form of suppositories. Pharmaceutical compositions comprising the compounds of the present invention in free form or in the form of a pharmaceutically acceptable salt, together with at least one pharmaceutically acceptable carrier or diluent, can be prepared in conventional manner by mixing, granulating or coating methods. For example, oral compositions may be tablets or gelatin capsules containing the active ingredient together with a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; for tablets, c) binders such as aluminum magnesium silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; optionally, d) disintegrants such as starch, agar, alginic acid, its sodium salt, or effervescent mixtures; and / or e) absorbents, colorants, flavorings, and sweeteners. Injectable compositions may be aqueous isotonic solutions or suspensions, and suppositories may be prepared from fatty emulsions or suspensions. The compositions may be sterilized and / or contain auxiliary substances such as preservatives, stabilizers, wetting agents or emulsifiers, solution enhancers, salts for adjusting osmotic pressure, and / or buffers. In addition, they may also contain other therapeutically valuable substances. Formulations suitable for transdermal application contain an effective amount of the compound of the present invention together with a carrier. The carrier may contain an absorbable pharmacologically acceptable solvent to assist penetration through the host's skin. For example, the transdermal device may be in the form of a bandage, which may include a backing member, a reservoir containing the compound, which may have a carrier, a rate-controlling barrier for delivering the compound to the host's skin at a controlled and predetermined rate over an extended period of time, and a means for fixing the device to the skin. Matrix transdermal formulations may also be used.Suitable formulations for topical application, e.g., to the skin and eyes, are preferably aqueous solutions, ointments, creams, or gels well known in the art, which may contain solubilizers, stabilizers, tonicity-increasing agents, buffers, and preservatives.

[0086] The compounds of the present invention can be administered in a therapeutically effective amount in combination with one or more therapeutic agents (pharmaceutical combinations). Non-limiting examples of compounds that can be used in combination with the compounds of the present invention include known antimalarial drugs, such as proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, ampicillin, sulfonamides, artemisinin, artefren, artemether, artesunate, primaquine, pyronaridine, KAE-609, and KAF-156.

[0087] When the compounds of the invention are administered in conjunction with other treatments, the dosage of the co-administered compounds will, of course, vary depending on the type of co-drug used, the particular drug used, the condition being treated, etc.

[0088] In one embodiment, the present invention provides a kit comprising two or more separate pharmaceutical compositions, at least one of which comprises a compound of the present invention. In one embodiment, the kit comprises a means for keeping the compositions separate, such as a container, a divided bottle, or a divided foil packet. An example of such a kit is a blister pack typically used for packaging tablets, capsules, and the like.

[0089] The kits of the invention can be used to administer different dosage forms (e.g., oral and parenteral), to administer the separate compositions at different dosage intervals, or to titrate the separate compositions relative to one another. To aid compliance, the kits of the invention typically include directions for administration.

[0090] In the combination therapy of the present invention, the compound of the present invention and the other therapeutic agent may be manufactured and / or formulated by the same or different manufacturers. Furthermore, the compound of the present invention and the other therapeutic agent may be combined into a combination therapy (i) prior to release of the combination product to the physician (e.g., in the case of a kit containing the compound of the present invention and the other therapeutic agent); (ii) by the physician (or under the physician's guidance) immediately prior to administration; or (iii) by the patient themselves, e.g., during sequential administration of the compound of the present invention and the other therapeutic agent.

[0091] Terms such as "co-administration" or "administration in combination," as used herein, are meant to encompass the administration of selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are not necessarily administered by the same route of administration or at the same time.

[0092] The term "pharmaceutical combination," as used herein, refers to a product obtained by mixing or combining two or more active ingredients, and includes both fixed and non-fixed combinations of active ingredients. The term "fixed combination" means that the active ingredients, e.g., a compound of Formula I, and an auxiliary agent are both administered to a patient simultaneously in the form of a single entity or dosage. The term "non-fixed combination" means that the active ingredients, e.g., a compound of Formula I, and an auxiliary agent are both administered to a patient simultaneously, in parallel, or alternatively sequentially, as separate entities without any specific time limit, such that such administration provides therapeutically effective levels of the two compounds in the patient's body. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0093] The compounds of the present invention can be administered simultaneously with, before, or after one or more other therapeutic agents. The compounds of the present invention can be administered separately, by the same or different administration route, or together with other agents in the same pharmaceutical composition. Therapeutic agents are, for example, compounds, peptides, antibodies, antibody fragments, or nucleic acids that are therapeutically active or enhance therapeutic activity when administered to a patient in combination with a compound of the present invention.

[0094] Processes for Making the Compounds of the Invention The present invention also includes processes for preparing the compounds of the present invention. In the reactions described, reactive functional groups, such as hydroxy, amino, imino, thio, or carboxy groups, may need to be protected, if desired, in the final product to avoid undesired participation in the reaction. Conventional protecting groups can be used in accordance with standard practice; see, for example, T.W. Greene and P.G.M.Wuts in "Protective Groups in Organic Chemistry," John Wiley and Sons, 1991.

[0095] Compounds of formula Ia can be prepared by proceeding as in Reaction Scheme 1, where L, Z, Y 1 , R 1 , R 2 , R 3 , n, m are as defined in the Summary of the Invention. The following reaction schemes are provided to illustrate, but not to limit, the description of the synthesis of compounds of the invention.

[0096] Reaction Scheme 1: General synthetic route The compounds of the present invention can be prepared by organic synthesis methods known to those skilled in the art with reference to the following reaction schemes and examples: A general method for synthesizing compounds of formula (Ia) is provided in Scheme I below. Formula (Ia): [ka]

[0097] Scheme (I). General method for synthesizing compounds of formula (Ia). [ka] Scheme I shows a general method for synthesizing many compounds of formula (Ia) from commercially available intermediates described herein. The iodo-bromo-imidazothiadiazole core can be selectively reacted with secondary cyclic amines at the bromo position under typical SnAr conditions in the presence of base. The secondary amines can be selectively reacted with various functional groups, R 3 The intermediate from the SnAr reaction can be further reacted with aryl and heteroaryl boronic acids under typical Suzuki coupling conditions using a palladium catalyst and base. The boronic acid compounds can also contain ortho-substitutions and one or two additional substituents, such as methyl, isopropyl, alkoxy, or fluoro. Finally, the amine is deprotected using typical conditions for removing the N-Boc group, such as trifluoroacetic acid, hydrochloric acid, or formic acid.

[0098] Detailed descriptions of the synthesis of compounds of the present invention are provided in the Examples below.

[0099] Further Processes for Making Compounds of the Invention The compounds of the present invention can be prepared as pharmaceutically acceptable acid addition salts by reacting the free base form of the compound with a pharmaceutically acceptable inorganic or organic acid. Alternatively, pharmaceutically acceptable base addition salts of the compounds of the present invention can be prepared by reacting the free acid form of the compound with a pharmaceutically acceptable inorganic or organic base. Alternatively, salt forms of the compounds of the present invention, such as fumarate salts, can be prepared using salts of the starting materials or intermediates.

[0100] The free acid or free base forms of the compounds of the present invention can be prepared from the corresponding base addition salt or acid addition salt, respectively. For example, a compound of the present invention in the form of an acid addition salt can be converted to the corresponding free base by treating with a suitable base (e.g., ammonium hydroxide solution, sodium hydroxide, etc.). A compound of the present invention in the form of a base addition salt can be converted to the corresponding free acid by treating with a suitable acid (e.g., hydrochloric acid, etc.).

[0101] The unoxidized forms of the compounds of the invention can be prepared from the N-oxides of the compounds of the invention by treatment with a reducing agent (e.g., sulfur, sulfur dioxide, triphenylphosphine, lithium borohydride, sodium borohydride, phosphorus trichloride, tribromide, etc.) in a suitable inert organic solvent (e.g., acetonitrile, ethanol, aqueous dioxane, etc.) at 0-80°C.

[0102] Prodrug derivatives of the compounds of the present invention can be prepared by methods known to those skilled in the art (e.g., for further details, see Saulnier et al., (1994), Bioorganic and Medicinal Chemistry Letters, Vol. 4, p. 1985). For example, suitable prodrugs can be prepared by reacting an underivatized compound of the present invention with a suitable carbamylating agent (e.g., 1,1-acyloxyalkylcarbanochloridate, para-nitrophenyl carbonate, etc.).

[0103] Protected derivatives of compounds of the invention can be made by means known to those skilled in the art. A detailed description of the techniques applicable to the creation of protecting groups and their removal can be found in T.W. Greene, "Protecting Groups in Organic Chemistry," 3 rd edition, John Wiley and Sons, Inc., 1999.

[0104] Compounds of the present invention may be conveniently prepared, or formed during the process of the invention, as solvates (e.g., hydrates). Hydrates of compounds of the present invention may be conveniently prepared by recrystallization from an aqueous / organic solvent mixture, using organic solvents such as dioxin, tetrahydrofuran or methanol.

[0105] Any asymmetric atom (e.g., carbon, etc.) of the compounds of the present invention can be present in racemic or enantiomerically enriched, for example, in the (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R)- or (S)-configuration. Substituents of atoms having unsaturated double bonds may, where possible, be present in cis-(Z)- or trans-(E)-form.

[0106] Thus, as used herein, the compounds of the invention may be in the form of one of the possible stereoisomers, rotamers, atropisomers, tautomers or mixtures thereof, for example, as substantially pure geometric (cis or trans) stereoisomers, diastereomers, optical isomers (enantiomers), racemates or mixtures thereof.

[0107] Any resulting mixture of stereoisomers can be separated on the basis of the physical chemical differences of the components into pure or substantially pure geometric or optical isomers, diastereomers, racemates, for example, by chromatography and / or fractional crystallization.

[0108] Any racemic compounds or intermediates of the present invention obtained can be separated into their optical antipodes by known methods, for example, by separating their diastereomeric salts obtained with optically active acids or bases, liberating the optically active acidic or basic compounds. Thus, particularly basic moieties can be used to separate the compounds of the present invention into their optical antipodes, for example, by fractional crystallization of salts formed with optically active acids, such as tartaric acid, dibenzoyltartaric acid, diacetyltartaric acid, di-O,O'-p-toluoyltartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid. Racemic compounds or racemic intermediates of the present invention can also be resolved by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0109] In summary, compounds of formula Ia are (a) the process of Reaction Scheme 1; and (b) optionally converting a compound of the invention into a pharmaceutically acceptable salt; (c) optionally converting a salt form of a compound of the invention into a non-salt form; (d) optionally separating the individual isomers of the compounds of the invention from the mixture of isomers; (e) optionally converting the underivatized compounds of the invention into pharmaceutically acceptable prodrug derivatives; and (f) optionally converting a prodrug derivative of a compound of the invention into its underivatized form. It can be made by a process including:

[0110] The present invention further includes any variation of the process of the present invention in which intermediates obtained at any stage thereof are used as starting materials to carry out the remaining steps, or in which starting materials are formed in situ under the reaction conditions, or in which reaction components are used in the form of their salts or optically pure substances. The compounds and intermediates of the present invention can also be converted into each other according to methods generally known to those skilled in the art. Unless the production of a starting material is specifically described, the compounds are known or can be prepared analogously to methods known in the art or as disclosed in the examples below.

[0111] Those of skill in the art will recognize that the above transformations are only representative of methods for preparing the compounds of the present invention, and that other well-known methods can similarly be used. [Example]

[0112] List of abbreviations AcOH acetic acid Alloc-Cl Allyl chloroformate B2Pin2 Bis(pinacolato)diboron br Wide signal BnBr benzyl bromide BnNH2 benzylamine BnOH benzyl alcohol B(O i Pr)3 Triisopropyl borate B(OMe)3 trimethyl borate (Boc)2O Di-tert-butyl dicarbonate Cbz-Cl Benzyl chloroformate CDCl3 chloroform-d d double line DAST Diethylaminosulfur trifluoride DCM dichloromethane DEA Diethylamine DIBAL Diisobutylaluminum hydride DIPEA Diisopropylethylamine DMAP 4-dimethylaminopyridine DME 1,2-dimethoxyethane DMF Dimethylformamide DMP Dess-Martin Periodinane DMSO dimethyl sulfoxide DPPA Diphenylphosphoryl azide equiv. Et3N Triethylamine Et2O diethyl ether EtMgBr Ethyl magnesium bromide EtOAc ethyl acetate EtOH ethanol Fe(acac)3Tis(acetylacetonate)iron(III) Fmoc Fluorenylmethyloxycarbonyl Grubbs II (1,3-bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphosphine)ruthenium h septet H2O Water HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Hexafluorophosphate oxide I2 Iodine IPA 2-propanol IPAm Isopropylamine i-PrMgCl Isopropyl magnesium chloride KHMDS Potassium bis(trimethylsilyl)amide KHSO4 Potassium hydrogen sulfate K2CO3 Potassium Carbonate K2OsO4 Potassium osmate(VI) K2S2O4 Potassium Dithionite K3Fe(CN)6 Potassium ferricyanide K3PO4 Tripotassium phosphate KI potassium iodide KOAc Potassium Acetate KOH Potassium hydroxide KO t Bu potassium tert-butoxide LDA Lithium diisopropylamide LiAlH4 Lithium Aluminum Hydride LiBH4 Lithium borohydride LiHMDS Lithium hexamethyldisilazide LiOH Lithium hydroxide m multiplet mCPBA metachloroperbenzoic acid Me2NH Dimethylamine MeCN acetonitrile MeMgBr Methylmagnesium bromide MeI methyl iodide MeOH Methanol MeSO2NH2 Methanesulfonamide MTBE Methyl tert-butyl ether MS mass spectrometry MsCl methanesulfonyl chloride MW microwave N normality N2 nitrogen NBS N-Bromosuccinimide n-BuLi n-butyllithium Na2CO3 Sodium Carbonate NaBH(OAc)3 Sodium triacetoxyborohydride NaCN Sodium cyanide NaH sodium hydride NaHCO3 Sodium Bicarbonate NaN3 Sodium Azide Na2SO4 Sodium Sulfate NCS N-chlorosuccinimide NH4Cl Ammonium chloride (NH4)2CO3 Ammonium Carbonate NH4HCO2 Ammonium Formate NH4OH Ammonium hydroxide NMO 4-Methylmorpholine N-oxide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance spectroscopy OsO4 Osmium tetroxide p quintet Pd / C Palladium Carbon Pd(dppf)Cl2 1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride Pd(dtbpf)Cl2 [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) Pd(PPh3)4 tetrakis(triphenylphosphine)palladium(0) Ph3P Triphenylphosphine PhMe Toluene q quartet s single line Red-Al Sodium bis(2-methoxyethoxy)aluminum dihydride Rf retention factor Rochelle Salt Potassium Sodium Tartrate Tetrahydrate RockPhos 2-Di(tert-butyl)phosphino-2',4',6'-triisopropyl-3-methoxy-6-methylbiphenyl t triple line TBAB Tetra-n-butylammonium bromide TBDMS-Cl tert-butyldimethylsilyl chloride t-BuLi tert-butyllithium t-BuOH tert-butyl alcohol T3P 1-Propanephosphonic anhydride TBAF Tetra-n-butylammonium fluoride TMEDA N,N,N',N'-Tetramethylethylenediamine TFA trifluoroacetic acid THF tetrahydrofuran Ti(OEt)4 Titanium(IV) Ethoxide TLC thin layer chromatography TsCl 4-toluenesulfonyl chloride Zn Zinc metal

[0113] General synthetic procedure The compounds described herein can be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0114] All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed. 1952, Methods of Organic Synthesis, Thieme, Volume 21).

[0115] The compounds of the present invention are prepared from publicly available compounds using procedures known to those skilled in the art in light of the examples and schemes provided herein.

[0116] Within the scope of this specification, unless the context dictates otherwise, only readily removable groups that are not constituents of the particular desired end product of the compounds of the invention will be referred to as "protecting groups".The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are described, for example, in Science of Synthesis: Houben-Weyl Methods of Molecular Transformation, Georg Thieme Verlag, Stuttgart, Germany, 2005, 41627 pp. (URL: http: / / www.science-of-synthesis.com (Electronic Version, 48 Volumes)); J.F.W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; T.W. Greene and P.G.W. Buts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, "The Peptides", Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, "Methoden der Organischen Chemie" (Methods of Organic Synthesis); Chemistry), Houben Weyl, 4th edition, Volume 15 / I, Georg Thieme Verlag, Stuttgart 1974; H.-D. Jakubke and H. Jeschkeit, "Aminosaeuren, Peptide, Protein" (Amino acids, Peptides, Proteins), Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982; and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide und Derivate" (Chemistry of Carbohydrates: Monosaccharides and Derivatives), Georg Thieme Verlag, Stuttgart 1974.A characteristic of protecting groups is that they can be easily removed (i.e. without the occurrence of undesired secondary reactions), for example by solvolysis, reduction, photolysis or alternatively under physiological conditions (e.g. by enzymatic cleavage).

[0117] As used herein, the term "salt(s)" refers to an acid addition or base addition salt of a compound of the present invention. "Salt" specifically includes "pharmaceutically acceptable salts." The term "pharmaceutically acceptable salts" refers to salts that retain the biological effectiveness and properties of the compound of the present invention, and which are typically not biologically or otherwise undesirable. In many cases, the compounds of the present invention are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0118] Pharmaceutically acceptable base addition acids can be formed with inorganic and organic acids.

[0119] Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0120] Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic acid, and the like.

[0121] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0122] Inorganic bases from which salts can be derived include, for example, ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper. Particularly suitable salts include ammonium, potassium, sodium, calcium, and magnesium salts.

[0123] Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, etc. Particular organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0124] In another embodiment, the present invention provides a compound of the present invention in the form of acetate, ascorbate, adipate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, caprate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, glutamate, glutarate, glycolate, hippurate, hydroiodide / iodide, isethionate, They are provided in the form of lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, mucate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, sebacate, stearate, succinate, sulfosalicylate, sulfate, tartrate, tosylate, triphenylacetate, trifluoroacetate or xinafoate. The mixtures of isomers obtained according to the invention can be separated into the individual isomers in a manner known per se. Diastereoisomers can be separated, for example, by partition between multiphase solvent mixtures, recrystallization and / or chromatographic separation, for example on silica gel or medium pressure liquid chromatography, for example on reverse phase columns; racemates can be separated, for example, by salt formation with an optically pure salt-forming reagent and separation of the resulting mixture of diastereoisomers, for example by fractional crystallization or chromatography on optically active column material.

[0125] Any formula provided herein is also intended to represent the unlabeled form and isotopically labeled form of the compound.Isotopically labeled compounds have the structure shown by the formula provided herein, except that one or more atoms are replaced by atoms with selected atomic mass or mass number.The isotopes that can be incorporated into the compounds of the present invention include, for example, hydrogen isotopes.

[0126] Additionally, certain isotopes, especially deuterium (i.e. 2 Incorporation of H or D) can result in certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced required dosage, or improved therapeutic index or tolerability. In this context, it is understood that deuterium is considered a substituent of the compounds of the present invention. The concentration of deuterium can be defined by the isotopic enrichment factor. As used herein, the term "isotopic enrichment factor" refers to the ratio between the isotopic abundance and the natural abundance of a particular isotope. When a substituent in a compound of the invention is designated as deuterium, such compound has, for each designated deuterium atom, an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation). It is understood that the term "isotopic enrichment factor" can be applied to any isotope in the same manner as described for deuterium.

[0127] Other examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as 3 H, 11 C. 13 C. 14 C.15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 123 I, 124 I, 125 Therefore, the present invention includes, for example, 3 H and 14 Radioactive isotopes such as C or 2 H and 13 It should be understood that compounds incorporating any one or more of the foregoing isotopes are included, including those in which non-radioactive isotopes such as C are present. Such isotopically labeled compounds may be useful in drug or substrate tissue distribution assays or metabolic studies, including radioactive treatment of patients. 14 C), reaction kinetic studies (e.g., 2 H or 3 H), positron emission tomography (PET) or single photon emission computed tomography (SPECT). 18 F or labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the accompanying examples and preparations using appropriate isotopically labeled reagents in place of previously used non-labeled reagents.

[0128] Intermediates and final products can be worked up and / or purified using standard methods, eg chromatographic methods, distribution methods, (re-)crystallization, and the like.

[0129] [Table 1]

[0130] [Table 2]

[0131] X-ray diffraction The X-ray powder diffraction (XRPD) patterns described herein areα The XRPD patterns were recorded on a Bruker D8 Advance diffractometer using radiation from 2° to 40° (2-theta).

[0132] Those skilled in the art will understand that X-ray diffraction patterns can be obtained with measurement errors that depend on the measurement conditions used. In particular, it is generally known that the intensities of X-ray diffraction patterns can vary depending on the measurement conditions used. Furthermore, it should be understood that relative intensities can also vary depending on the experimental conditions and the wavelength of X-ray radiation used. The agreement of the 2-theta diffraction angles between the sample and the reference is within 0.2° for the same crystalline form, and the degree of measurement error, such as that related to the aforementioned diffraction angles, must be taken into account. Therefore, it should be understood that the crystalline form of the present invention is not limited to a crystalline form that provides an X-ray diffraction pattern that is completely identical to the X-ray diffraction pattern shown in the accompanying drawings disclosed herein. Any crystalline form that provides an X-ray diffraction pattern substantially identical to that disclosed in the accompanying drawings is within the scope of the present invention. The ability to confirm the substantial identity of X-ray diffraction patterns is within the understanding of those skilled in the art.

[0133] thermogravimetric analysis The TGA instrument used to test the crystalline form was a TA Discovery TGA. 10-20 milligram samples were analyzed over a temperature range of 30°C to approximately 300°C at a heating rate of 10°C per minute.

[0134] Differential scanning calorimetry (DSC) The DSC instrument used to test the crystal form was a TA Discovery DSC. The DSC cell / sample chamber was purged with ultra-high purity nitrogen gas at 20–50 ml / min. The instrument was calibrated with high-purity indium. Samples were placed in open aluminum DSC pans and measured against an empty reference pan. Approximately 1–3 mg of sample powder was placed on the bottom of the pan and gently tapped to contact the pan. The sample weight was accurately measured and recorded to the nearest hundredth of a milligram. The instrument was programmed to heat at 10°C per minute over a temperature range of 0°C to 300°C.

[0135] The present invention is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are well established in the art, and demonstration of efficacy in these assays is generally considered predictive of efficacy in subjects.

[0136] Examples 1-3: Intermediates Compound 1-0: 2-Bromo-5-iodoimidazo[2,1-b][1,3,4]thiadiazole [ka] Compound 1-0 was prepared in the following manner. [ka] To compound 1-1 (500 g, 4.95 mol) in MeOH (5 L) was added NaHCO (830.9 g, 9.89 mol) at room temperature, the mixture was cooled to 0-5 °C, and bromine (792.0 g, 4.95 mol) was added dropwise over 1 h. The mixture was then warmed to room temperature and stirred for 3 h. The solid was filtered and washed with MeOH (500 mL). The solid was then slurried in HO (10 L) for 1 h, collected, washed with HO (1 L), and the solid was slurried in MeOH (1.5 L), filtered, and washed with MTBE (1 L) to give 554.0 g of compound 1-2 as a solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.51(brs,2H).LC-MS=179.9[M+H] + .

[0137] [ka] Compound 1-2 (500 g, 2.78 mol) was added to a 1:1 mixture of HO and EtOH (5 L), followed by the addition of 44% aqueous 2-chloroacetaldehyde (1425.9 g, 7.78 mol) at room temperature over 15 minutes. The reaction mixture was heated at reflux for 1 hour and stirred for 48 hours. After completion of the reaction, the reaction mixture was quenched with 8% aqueous NaHCO (5 L), and EtOAc (10 L) was added to it. The mixture was stirred at room temperature for 10 minutes. The reaction mixture was filtered through a CELITE pad, and the pad was washed with EtOAc (1 L). The organic layer was separated, and the aqueous layer was extracted with EtOAc (1 L × 2). The combined organic layers were concentrated and purified by normal-phase chromatography using a running gradient of 16.7–25% EtOAc / heptane to give 88.5 g of compound 1-3 as a solid. 1 H NMR(300MHz,DMSO-d6):δ ppm 8.22(d,J=1.2Hz,1H),7,39(d,J=0.8Hz,1H).LC-MS=203.9[M+H] + .

[0138] [ka] Compound 1-3 (50.0 g, 245 mmol) and NIS (66.1 g, 294 mmol) in DMF (500 mL) were added in one portion, and the resulting mixture was stirred for 2.5 h. Another portion of NIS (11.0 g, 49 mmol) was added and stirred for an additional 1.5 h. The reaction mixture was diluted with EtOAc (2.0 L), and then washed with aqueous NaSO (500 mL). The organic layer was washed with ice-cold HO (3 × 250 mL), brine (250 mL), dried over NaSO, filtered, and concentrated. The residue was stirred with MeCN (100 mL) for 30 min. The solid was filtered and washed with MeCN (50 mL) to give 40.4 g of compound 1 as a solid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.43(s,1H).LC-MS=329.7[M+H] + .

[0139] Compound 2-0a: tert-butyl ((4-hydroxypiperidin-4-yl)methyl)carbamate [ka] Compound 2-0a was prepared in the following manner. [ka] NaH (27.5 g, 687.5 mmol) was added portionwise to DMSO (1000 mL) at 18 °C under N, and trimethylsulfoxonium iodide (127.9 g, 581.1 mmol) was added slowly portionwise within 1 h. The resulting solution was warmed to room temperature and maintained for 1 h. Compound 2-1 (100 g, 528.3 mmol) in DMSO (100 mL) was added at 18 °C and stirred at room temperature for 2 h. The solution was then quenched with saturated NH4Cl solution (500 mL) at 10 °C and extracted with MTBE (1 L × 4). The combined organic layers were washed with HO (300 mL × 3), brine (200 mL × 2), and concentrated to give 120.2 g of compound 2-2 as a yellowish liquid. 1 H NMR(400MHz,DMSO-d6):δ ppm 7.26-7.38(m,5H),3.59(s,2H),2.55-2.67(m,5H),1.82-1.89(m,2H),1.57-1.60(m,2H).LC-MS=204.1[M+H] + .

[0140] [ka] Compound 2-2 (120.2 g, 514 mmol) in MeOH (720 mL), aqueous ammonia (1440 mL, 28%) was added dropwise at 0 °C, and then the resulting mixture was stirred at room temperature for 16 h. The mixture was extracted with DCM (800 mL × 3), and the combined organic layers were washed with NaOH (1 N, 200 mL × 2), brine (200 mL), dried over NaSO, and concentrated to give 144.2 g of compound 2-3 as a solid, which was used in the next step without further purification.

[0141] [ka] Compound 2-3 (144.2 g, crude) was dissolved in DCM (1.4 L), (Boc)O (140.4 g, 644 mmol) was added dropwise at room temperature, and the resulting solution was stirred for 3 h. The reaction mixture was concentrated and purified by normal phase chromatography to give 129.6 g of compound 2-4 as a solid. 1 H NMR(400MHz,CDCl3):δ ppm 7.24-7.32(brs,5H),4.90(s,1H),3.53(s,2H),3.15(d,J=6.0Hz,2H),2.59-2.6 2(m,2H),2.30-2.40(m,3H),1.56-1.67(m,4H),1.44(s,9H).LC-MS=321.2[M+H] + .

[0142] [ka] Compound 2.4 (69.0 g, 215.3 mmol) was dissolved in EtOH (510 mL), Pd(OH) (21.0 g, 10%) was added under N, the resulting mixture was exchanged with H, the mixture was stirred for 18 h, the mixture was filtered through a pad of CELITE, washed with DCM (100 mL), concentrated, stirred in MTBE (100 mL), and filtered to give 35.2 g of compound 2a as a solid. 1 H NMR(400MHz,CDCl3):δ ppm 4.95(brs,1H),3.13-3.21(d,J=6.0Hz,2H),2.91-2.97(m,2H),2.82-2.87 (m,2H),2.08(brs,2H),1.47-1.54(m,4H),1.43(s,9H).LC-MS=231.1[M+H] + .

[0143] Compound 2-0b: tert-butyl (4-(hydroxymethyl)piperidin-4-yl)carbamate [ka] Compound 2-0b was prepared in the following manner. [ka] To a solution of 1-benzylpiperidin-4-one (20.0 g, 105.6 mmol) in EtOH:HO (280 mL, 1:1) was added (NH)CO (101.4 g, 1056.7 mmol), followed by NaCN (15.5 g, 316.8 mmol). The reaction mixture was heated at 60 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with HO, and then filtered. The filtrate was washed with HO and EtOH and dried under vacuum to give 25 g of compound 2-2 as a solid. The crude compound was used in the next step without further purification. 1 H NMR(300MHz,DMSO-d6)δ 8.33(s,1H),7.38-7.06(m,5H),3.46(s,2H),2.67(dt,J=11.5,4.0,4.0Hz,2H),2.34-2. 15(m,2H),1.79(td,J=12.4,11.9,4.1Hz,2H),1.47(d,J=13.2Hz,2H).LC-MS=260.1[M+H] + , retention time = 0.35 min (method P).

[0144] [ka] To a solution of KOH (75.0 g, 1532.9 mmol) in HO (320 mL) was added compound 2-2 (26.5 g, 102.1 mmol), and the reaction mixture was heated at 100° C. for 24 hours. The reaction mixture was cooled to 0° C., and the pH was adjusted to 6 using 6N HCl solution. The precipitated product was filtered, washed with HO and MTBE, and dried under vacuum. The resulting product was co-distilled with PhMe to give 18 g of compound 2-3 as a solid. LC-MS=234.9 [M+H] + , retention time = 0.13 min; HPLC: 96.66%, retention time = 2.62 min (method P).

[0145] [ka] To a solution of compound 2-3 (18 g, 76.9 mmol) in anhydrous THF (600 mL) was added LiAlH (9.71 g, 256.08 mmol) portionwise at 0 °C and heated at 66 °C for 3 h. The reaction mixture was quenched with HO and 1N NaOH solution and filtered. The resulting solid was washed with EtOAc, and the solvent was concentrated to give 14 g of compound 2-4 as an oil. 1 H NMR(400MHz,DMSO-d6)δ 7.44-7.02(m,5H),4.51(s,1H),3.44(s,2H),3.11(s,1H),2.46-2.23(m,3H ),1.46(ddd,J=15.9,8.0,3.0Hz,2H),1.27-1.18(m,2H).LC-MS=234.9[M+H] + , retention time = 0.13 min.

[0146] [ka] To a stirred solution of compound 2-4 (14 g, 63.54 mmol) in anhydrous DCM (200 mL), (Boc)2O (15.2 g, 69.89 mmol) was added dropwise and heated at room temperature for 16 h. The reaction mixture was concentrated, and the crude compound was purified by normal phase chromatography using a running gradient of 5-10% MeOH / DCM. The resulting product was washed with pentane and filtered to give 9.3 g of compound 2-5 as a solid. 1 H NMR(300MHz,CDCl3)δ 7.39-7.17(m,5H),4.53(s,1H),3.68(s,1H),3.55(d,J=20.6Hz,2H),2.62(ddd,J=17.5,6.6,4.4 Hz,2H),2.36-2.11(m,1H),1.98-1.77(m,2H),1.78-1.64(m,2H),1.44(s,9H).LC-MS=221.0[M+H] + , retention time = 0.13 min.

[0147] [ka] To a stirred solution of compound 2-5 in MeOH (150 mL) was added HCOONH4 (11.0 g, 174.14 mmol) followed by 10% Pd / C (0.93 g, 10% ww) and heated at 60° C. for 2 h. The reaction mixture was filtered through a pad of CELITE, washed with MeOH, and concentrated to give 7 g of compound 2b as a solid. 1 H NMR(300MHz,DMSO-d6)δ 6.11(s,1H),4.71-4.40(m,1H),3.35 -3.30(m,4H),2.64-2.52(m,4H),1.82(d,J=13.1Hz,2H),1.36(s,9H),1.35-1.31(m,1H).LC-MS=321.1[M+H] + , retention time = 1.27 min.

[0148] Compound 3-0: tert-butyl ((4-hydroxy-1-(5-iodoimidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methyl)carbamate [ka] Compound 3-0 was prepared in the following manner. [ka] Compound 2a (83.8 g, 363.7 mmol) and compound 1 (80 g, 242.5 mmol) were dissolved in DMSO (800 mL), DIPEA (62.6 g, 485 mmol) was added dropwise, the resulting mixture was heated to 110 °C, the mixture was stirred for 3 h, the mixture was cooled to room temperature, HO (800 mL) was added, extracted with EtOAc (1 L × 4), the combined organic layer was washed with HO (200 mL × 3), brine (200 mL × 3), dried over NaSO and concentrated, and the residue was stirred in MeCN:MeOH (10:1, 500 mL) to give 67.1 g of compound 3 as a solid. 1H NMR(400MHz,MeOD-d4):δ ppm 7.06(s,1H),2.69-3.72(m,2H),3.45-3.52(m,2H),3.11(s,2H),1.63-1.76(m,4H),1.44(s,9H).LC-MS=480.0[M+H] + .

[0149] Example 4-0: 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ka] Compound 4-0 was prepared in the following manner. [ka] A mixture of compound 3 (40 mg, 0.083 mmol), (6-isopropyl-2-methoxypyridin-3-yl)boronic acid (32.5 mg, 0.167 mmol), PdCl(dppf)-DCM complex (3.41 mg, 4.17 μmol), and KPO (53.1 mg, 0.250 mmol) in anhydrous dioxane (1 mL) and HO (0.2 mL) was flushed with N for several minutes, then sealed and heated at 80 °C for 3 h. The crude material was purified by normal-phase chromatography (4 g column) using a running gradient of 0–50% (3:1 EtOAc:EtOH) / heptane to give 39.4 mg of compound 4-1 as a solid. LC-MS = 503.3 [M+H] + .

[0150] [ka] N-Boc deprotection method: Route A via TFA conditions: Compound 4-1 (148 mg, 0.294 mmol) was dissolved in DCM (1 mL) and TFA (0.5 mL, 6.53 mmol) was added. The reaction was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo, then redissolved in DCM and saturated Na2CO3 solution was added. The aqueous layer was extracted twice with DCM and then twice with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated. The crude material was purified by preparative HPLC to give 63.7 mg of compound 4-2 as a solid.

[0151] Route B under HCl conditions: To a solution of compound 4-1 (39 mg, 0.078 mmol) in MeOH (0.5 mL) was added HCl 4M in dioxane (0.5 mL, 2.0 mmol). The reaction was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and then purified by preparative HPLC to give 18.2 mg of compound 4-2 as a solid.

[0152] Route C via TFA (free base) conditions: To a solution of compound 4-1 (150 mg, 0.298 mmol) in DCM (10 mL) was added TFA (0.6 mL) at 0 °C, and the reaction mixture was then stirred at room temperature for 2 h. The reaction was concentrated in vacuo. The residue was treated with 10% NaHCO3 at room temperature for 2 h, and the product was then extracted with 5% MeOH in DCM. The combined organic layers were washed with 10% NaHCO3, brine, dried over Na2SO4, and concentrated in vacuo. The resulting solid was triturated with pentane, filtered, and dried to give the desired product as the free base.

[0153] Preparation and characterization of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate salt and solid forms To a mixture of 30 mL of acetonitrile and 5 mL of water in a reactor, 3.0 g of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate (7.45 mmol) was added. A solution of 0.549 g of adipic acid (3.75 mmol) in 15 mL of acetonitrile / water (80:20) was added at 50°C within 90 minutes. The resulting suspension was kept stirring at 50°C for 2 hours, and then cooled to 25°C with stirring for another 12 hours. After filtration and washing with dry acetonitrile, the residue was dried under vacuum at 40°C for 8 hours. 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate was obtained as a solid.

[0154] Solid Form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate can be prepared by 1) heating a sample at least 10° C. above the melting point and cooling the sample to 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. or 2) by equilibrating a slurry of about 40 mg to about 100 mg of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate or Solid Form B in about 0.5 mL to about 1 mL of a solvent listed in Table 1 below at 25°C to 50°C for at least about 24 hours to about 28 days, filtering the solid, and drying in air for about 10 minutes. Solid Form A is slightly hygroscopic, absorbing about 0.4% water at 95% RH.

[0155] [Table 3]

[0156] Figure 1 provides the X-ray diffraction pattern of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate, with the peak list as shown in Table 2. Figure 2 provides the differential scanning calorimetry (DSC) thermogram scan of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. Figure 3 provides a TGA thermogram scan of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. Figure 4 shows a scanning electron microscope (SEM) image of crystalline form A of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate.

[0157] [Table 4]

[0158] Solid Form B can be prepared by: 1) dissolving Solid Form A in a minimum amount of acetone to dissolve Solid Form A at 60°C, cooling and stirring the solution in an ice bath, and filtering and drying the solid in air for approximately 10 minutes; 2) recrystallizing Solid Form A from a minimum amount of 1:1 methanol / water to dissolve Solid Form A at 60°C, cooling and stirring the solution in an ice bath, and filtering and drying the solid in air for approximately 10 minutes; 3) 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2, Solid Form B was obtained by recrystallization from precipitation of 1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate salt by the addition of DMSO to a solution of benzyl alcohol; and 4) precipitation of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate salt by the addition of methanol to a solution of benzyl alcohol. Solid Form B is a highly crystalline material with a melting point of approximately 214°C. Solid Form B is only slightly hygroscopic, absorbing approximately 0.3% water at 95% RH. Figure 5 provides the X-ray diffraction pattern of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate, with the peak list as shown in Table 3. Figure 6 provides the differential scanning calorimetry (DSC) thermogram scan of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate. FIG. 7 provides a TGA thermogram scan of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate.FIG. 8 shows a scanning electron microscope (SEM) photograph of crystalline form B of 4-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol (2:1) adipate.

[0159] [Table 5]

[0160] The following compounds were prepared by general synthetic route (I) using appropriate commercially available starting materials and are exemplified by compound 4-0. All starting materials and intermediates that are not commercially available and / or do not have published synthetic routes are exemplified by compounds herein. Compounds containing a stereocenter were either prepared from the appropriate chiral commercially available starting material or purified using the chiral preparative HPLC method listed below for the N-Boc intermediates prior to N-Boc deprotection.

[0161] [Table 6]

[0162] [Table 7]

[0163] [Table 8]

[0164] [Table 9]

[0165] [Table 10]

[0166] [Table 11]

[0167]

Table 12

[0168]

Table 13

[0169]

Table 14

[0170]

Table 15

[0171] Table 16

[0172]

Table 17

[0173]

Table 18

[0174]

Table 19

[0175] Table 20

[0176] Table 21

[0177] [Table 22]

[0178] [Table 23]

[0179] [Table 24]

[0180] [Table 25]

[0181] [Table 26]

[0182] [Table 27]

[0183] Example 5-0: 2-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5-oxa-2,7-diazaspiro[3.4]oct-6-en-6-amine [ka] Compound 5-0 was prepared by the same route as used to prepare compound 4-0 using tert-butyl ((3-hydroxyazetidin-3-yl)methyl)carbamate, compound 1, and (2-methoxy-4-methylphenyl)boronic acid, followed by cyclization.

[0184] [ka] Compound 5-1 (38 mg, 0.091 mmol) and K2CO3 (50.2 mg, 0.363 mmol) were stirred in anhydrous DMSO (1 mL), followed by the addition of cyanogen bromide (14.43 mg, 0.136 mmol), and the reaction was stirred at room temperature for 1 h. The reaction mixture was then filtered and purified by preparative HPLC. The fraction obtained in formic acid solution was treated with aqueous Na2CO3 until the pH became strongly basic (pH > 11). The solution was then extracted twice with EtOAc, washed with brine, dried over Na2SO4, and concentrated to give 6.3 mg of compound 5-0 as a solid. 1 H NMR(500MHz,DMSO-d6)δ 7.98(d,J=7.8Hz,1H),7.45(s,1H),6.97(s,1H),6.87(d,J=7.7Hz,1H),6. 13(s,2H),4.50-4.21(m,4H),3.86(s,5H),2.35(s,3H).LC-MS=371.1[M+H] + .

[0185] The following compounds were prepared by the same route used to prepare compound 5-0 using the appropriate starting materials.

[0186] [Table 28]

[0187] Example 6-0: (3aS,5S,6S,7aR)-6-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol [ka] Compound 6-0 was prepared in the following manner. [ka] A solution of tert-butyl (1aR,2aR,5aS,6aS)-octahydro-4H-oxireno[2,3-f]isoindole-4-carboxylate (500 mg, 2.089 mmol) in MeOH (10 mL) and HO (2 mL) was treated with NaN (679 mg, 10.45 mmol) and NHCl (224 mg, 4.18 mmol). The reaction was warmed to 65 °C for 18 h, then cooled to room temperature, concentrated to remove MeOH, and extracted with DCM. The combined organic layers were passed through a phase separator and concentrated in vacuo to give an oil that crystallized on standing. The residue was taken up in EtO, and the resulting solid was isolated by filtration and dried to give 289 mg of compound 6-1. 1 H NMR(500MHz,DMSO-d6)δ 5.15(d,J=5.7Hz,1H),3.53(td,J=10.4,5.3Hz,1H),3.31-3.20(m,3H),3.06(dd,J=11.2,5.9Hz,2H),2.36(s,1H),2.17(dd ,J=11.5,6.2Hz,1H),1.89(t,J=9.8Hz,1H),1.78(d,J=12.1Hz,1H),1.52(d,J=13.1Hz,1H),1.39(s,9H),1.17-1.04(m,1H).

[0188] [ka] Compound 6-1 (289 mg, 1.024 mmol) was treated with HCl (1 M in dioxane) (4 mL, 4.00 mmol). The reaction was sealed and stirred at 20 °C for 3 h. The reaction was concentrated in vacuo under a stream of N to give 222 mg of compound 6-2.

[0189] [ka] To a solution of compound 1 (335 mg, 1.015 mmol) and compound 6-2 (222 mg, 1.015 mmol) in MeCN (4 mL) was added DIPEA (0.544 mL, 3.05 mmol). The reaction was sealed and stirred at 100 °C for 2 h, then cooled to room temperature and purified by normal phase chromatography using a running gradient of 0 to 100% EtOAc / heptane to give 349 mg of compound 6-3. 1 H NMR(500MHz,DMSO-d6)δ 7.08(s,1H),5.27-5.12(m,1H),3.59(dd,J=3.3,9.1Hz,2H),3.43(dt,J=5.6,10.2Hz,2H),3.25(d,J=10.0Hz,2H),2. 61(s,1H),2.41(s,1H),1.97(s,1H),1.92-1.77(m,1H),1.61(d,J=13.1Hz,1H),1.31-1.16(m,1H).LC-MS=432.1[M+H] + .

[0190] [ka] A mixture of compound 6-3 (149 mg, 0.346 mmol), (6-isopropyl-2-methoxypyridin-3-yl)boronic acid (135 mg, 0.691 mmol), PdCl(dppf)-DCM complex (28.2 mg, 0.035), and KPO (220 mg, 1.037 mmol) was flushed with N for several minutes, followed by the addition of dioxane (2.5 mL) and HO (0.5 mL). The vial was flushed with N for an additional minute, then sealed and heated at 80 °C for 3 h. The reaction was concentrated in vacuo and purified by normal-phase chromatography (24 g column) using a running gradient of 0–60% (3:1 EtOAc:EtOH) / heptane. The fractions were combined, concentrated in vacuo, and then triturated twice with DCM / heptane and then with MeOH / heptane. The resulting products were separated by chiral separation (Method 8) to give 18.2 mg of compound 6-4 peak 1 and 17.3 mg of compound 6-4 peak 2.

[0191] [ka] To a solution of single stereoisomer compound 6-4pk2 (17.3 mg, 0.038 mmol) in THF (1 mL) and HO (0.2 mL) was added PhP (15 mg, 0.057 mmol). The reaction was then heated to 40 °C for 2 h. An additional portion of PhP (15 mg, 0.057 mmol) was added and heated at 50 °C for 12 h. The reaction was concentrated in vacuo and purified by preparative HPLC to give 9.5 mg of compound 6. 1 H NMR(500MHz,DMSO-d6)δ 8.60(d,J=7.7Hz,1H),7.83(d,J=5.1Hz,3H),7.62(s,1H),7.01(d,J=7.8Hz,1H),4.02(s ,3H),3.64(qd,J=9.7,8.7,4.0Hz,3H),3.44-3.31(m,2H),2.98(h,J=6.9Hz,1H),2.89(s, 1H),2.72(s,1H),2.48(dd,J=12.4,5.8Hz,1H),2.09(q,J=6.0,4.8Hz,1H),2.03-1.94(m, 1H),1.69-1.60(m,1H),1.35(q,J=12.8Hz,1H),1.28(d,J=6.9Hz,6H).LC-MS=429.2[M+H] + .

[0192] The following compounds were prepared by the same route used to prepare compound 6-0 using the appropriate starting materials.

[0193] [Table 29]

[0194] Example 7-0: (9-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-9-azaspiro[5.5]undecan-3-yl)methanamine [ka] Compound 7-0 was prepared in the following manner. [ka] To a solution of tert-butyl 3-(aminomethyl)-2-oxa-9-azaspiro[5.5]undecane-9-carboxylate (100 mg, 0.352 mmol) in MeOH (1 mL) was added 4 M HCl in dioxane (1.319 mL, 5.27 mmol) and stirred for 1 h. The resulting white suspension was concentrated in vacuo and then partially dissolved in EtOH (1 mL), and compound 1 (116 mg, 0.352 mmol) and DIPEA (0.184 mL, 1.055 mmol) were added. The resulting suspension was heated to 80 °C for 18 h. The mixture was quenched with saturated NaHCO3 solution and extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by normal phase chromatography (4 g column) using a running gradient of 0-20% (DCM / (DCM / MeOH 8 / 2)) to give 59 mg of compound 7-1 as a beige foam. 1 H NMR(500MHz,MeOD-d4)δ 7.04(s,1H),3.87(dd,J=11.5,2.7Hz,1H),3.55-3.42(m,4H),3.33(dt,J=8.3,3.6Hz,1H),3.24(d,J=11.5Hz,1H),2.76 -2.62(m,2H),1.91(dt,J=13.3,3.2Hz,1H),1.86-1.75(m,2H),1.52-1.46(m,2H),1.45-1.35(m,3H).LC-MS=434.2[M+H] + .

[0195] [ka] To a solution of compound 7-1 (59 mg, 0.136 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (30.1 mg, 0.177 mmol) in dioxane was added Na2CO3 (477 μL, 0.953 mmol) and PdCl2(Ph3P)2 (4.78 mg, 6.81 μmol) under argon. The reaction was heated to 100 °C for 2 h. The mixture was quenched with saturated NaHCO3 solution, and then EtOAc was added. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by preparative HPLC to give 7.1 mg of compound 7-0 as a solid. 1 H NMR(500MHz,DMSO-d6)δ 8.21(dd,J=8.7,6.9Hz,1H),7.83(s,3H),7.53(s,1H),7.09(dd,J=11.4,2.6Hz,1H) ,6.92(td,J=8.4,2.6Hz,1H),3.92(s,3H),3.90(d,J=5.2Hz,1H),3.89-3.86(m,3H) ,3.56-3.43(m,8H),3.19(d,J=11.5Hz,1H),3.03-2.92(m,1H),2.89-2.79(m,1H),1 .91(d,J=12.9Hz,1H),1.76(t,J=4.9Hz,2H),1.55-1.34(m,5H).LC-MS=432.4[M+H] + .

[0196] The following compounds were prepared by the same route used to prepare compound 7-0 using the appropriate starting materials.

[0197] [Table 30]

[0198] [Table 31]

[0199] Example 8-0: 4-(aminomethyl)-1-(5-(2-(dimethylamino)-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ka] Compound 8-0 was prepared in the following manner. [ka] To a solution of 3-bromo-2-fluoro-6-methylpyridine (100 mg, 0.526 mmol) in dioxane (2.6 mL) was added B2Pin2 (200 mg, 0.789 mmol), KOAc (129 mg, 1.316 mmol), and PdCl2(dppf)-DCM complex (38.5 mg, 0.053 mmol) under argon. The reaction was heated to 90 °C for 2 h. The reaction mixture was quenched with saturated NaHCO3 solution and then diluted with EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (4 g column) using a running gradient of 0-10% MeOH / DCM to give 86 mg of compound 8-1 as an oil. LC-MS = 238.4 [M+H] + .

[0200] [ka] To a solution of compound 3 (50 mg, 0.104 mmol) and compound 8-1 (32.1 mg, 0.136 mmol) in dioxane (1 mL) was added Na2CO3 (0.365 mL, 0.730 mmol) and PdCl2(Ph3P)2 (3.66 mg, 5.22 μmol) under argon. The reaction was heated to 100 °C for 2 h. The mixture was quenched with saturated NaHCO3 solution and then diluted with EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (4 g column) using a running gradient of 0-20% MeOH / DCM to give 36 mg of compound 8-2 as a solid. LC-MS = 463.2 [M+H] + .

[0201] [ka] A solution of compound 8-2 (40 mg, 0.065 mmol) in dimethylamine 2M in THF (1 mL, 2.000 mmol) was heated to 140 °C under MW for 6 h. Additional dimethylamine 2M (500 μL) was added and the reaction was stirred at 140 °C for 2 h. The resulting solution was concentrated in vacuo and purified by normal phase chromatography (4 g column) using a running gradient of 0-20% MeOH / DCM to give 30 mg of compound 8-3. LC-MS = 488.0 [M+H] + .

[0202] [ka] To a solution of compound 8-3 (30 mg, 0.062 mmol) in MeOH (2 mL) was added HCl 4M in THF (200 μL, 0.800 mmol). The reaction was stirred at room temperature for 1 hour and then concentrated in vacuo. The resulting product was purified by preparative HPLC to give 26 mg of compound 8 as a solid. 1H NMR(400MHz,DMSO-d6)δ 7.79(d,J=7.9Hz,4H),7.35(s,1H),6.80(d,J=7.6Hz,1H),3.63(dt,J=13.2,4.2Hz,2H),3.44(dt,J=13.7 ,7.1Hz,2H),2.84(d,J=5.9Hz,2H),2.74(s,6H),2.42(s,3H),1.68(t,J=6.0Hz,4H).LC-MS=388.0[M+H]+.

[0203] Example 9-0: 4-(aminomethyl)-1-(5-(6-methyl-2-(methylthio)pyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ka] Compound 9-0 was prepared in the following manner. [ka] A solution of compound 8-2 (50 mg, 0.108 mmol) and methanethiol, sodium salt (37.9 mg, 0.540 mmol) in THF (2 mL) was heated to 120 °C for 1 h. Additional methanethiol sodium salt (20 mg) was added, and the reaction was heated at 120 °C for 1 h. The mixture was quenched with saturated NaHCO3 solution and diluted with EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (4 g column) using a running gradient of 0-100% EtOAc / cyclohexane to give 10 mg of compound 9-1 as an oil. LC-MS = 491.2 [M+H] + .

[0204] [ka] A solution of compound 9-1 (10 mg, 0.020 mmol) and HCl 4 M in THF (500 μL, 2.000 mmol) in MeOH (1 mL) was stirred at room temperature for 1 hour. The resulting solution was concentrated in vacuo. The crude product was purified by preparative HPLC to give 3.7 mg of compound 9-0. 1 H NMR(500MHz,DMSO-d6)δ 7.85(d,J=7.8Hz,1H),7.75(s,3H),7.39(s,1H),7.10(d,J=7.8Hz,1H),3.61(d,J=13.4Hz ,2H),3.49-3.37(m,2H),2.82(d,J=5.9Hz,2H),1.66(d,J=12.4Hz,4H).LC-MS=391.1[M+H] + .

[0205] Example 10-0: 3-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol [ka] Compound 10-0 was prepared in the following manner. [ka] A mixture of tert-butyl 1-oxa-5-azaspiro[2.5]octane-5-carboxylate (500 mg, 2.344 mmol) in MeOH (10 mL) and HO (2 mL) was treated with NaN (762 mg, 11.72 mmol) and NH Cl (251 mg, 4.69 mmol). The reaction was warmed to 65 °C for 18 h. The reaction was cooled to room temperature, concentrated in vacuo to remove MeOH, and extracted with DCM. The organic layer was passed through a phase separator and concentrated in vacuo to give 616.6 mg of compound 10-1 as an oil. LC-MS = 257.4 [M+H] + .

[0206] [ka] A mixture of compound 10-1 (616 mg, 2.403 mmol) in HCl in dioxane (4 mL, 16.00 mmol) was stirred at room temperature for 1 hour. The reaction mixture was dried under a stream of N to give 570.9 mg of compound 10-2. LC-MS = 157.3 [M+H] + .

[0207] [ka] To a mixture of compound 1 (793 mg, 2.403 mmol) and compound 10-2 (463 mg, 2.403 mmol) in MeCN (10 mL) was added DIPEA (1.287 mL, 7.21 mmol). The reaction was heated at 100 °C for 18 h. The reaction was cooled to room temperature and purified by normal phase chromatography using a running gradient of 0-100% EtOAc / heptane to give 789.7 mg of compound 10-3. LC-MS = 406.1 [M+H] + .

[0208] [ka] A mixture of compound 10-3 (180 mg, 0.444 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (113 mg, 0.666 mmol), and PdCl(dppf)-DCM complex (16.25 mg, 0.022 mmol) was placed under a N atmosphere. Dioxane (2 mL) and 2 M KPO (0.755 mL, 1.510 mmol) were then added. The reaction mixture was heated at 90 °C for 18 h. 1.5 equivalents of (4-fluoro-2-methoxyphenyl)boronic acid (113 mg, 0.666 mmol) and 0.05 equivalents of PdCl(dppf)-DCM complex (16.25 mg, 0.022 mmol) were then added, and the resulting mixture was heated at 90 °C for 5 h. The solution was diluted with MeOH / DCM, filtered through a pad of CELITE, and concentrated in vacuo. The crude material was purified by normal phase chromatography using a running gradient of 0-100% EtOAc / heptane to give 20.6 mg of compound 10-4. LC-MS=404.3 [M+H] + .

[0209] [ka] To a solution of compound 10-4 (20.6 mg, 0.051 mmol) in THF (2 mL) and HO (0.050 mL) was added polymer-bound triphenylphosphine (20.09 mg, 0.077 mmol) (approximately 3 mmol / g loading, therefore 26 mg added per 0.077 mmol). The reaction was placed on a shaker for 18 h. Next, 75 mg of polymer-bound triphenylphosphine (20.09 mg, 0.077 mmol) was added and placed on a shaker for an additional 18 h. The reaction was filtered and concentrated under N. The resulting crude material was purified by preparative HPLC to give 1.9 mg of compound 10. 1H NMR(500MHz,MeOD-d4)δ 8.26(t,J=7.7Hz,1H),7.69(s,1H),6.99(d,J=10.9Hz,1H),6.86(t,J=8.5Hz,1H),3.97(s,3H),3.84(d,J=12.1Hz,1H),3.69(d,J=13.5Hz, 1H),3.49(d,J=13.3Hz,1H),3.41(t,J=11.6Hz,1H),3.12-2.97(m,2H),2.15-2.03(m,1H),1.82(dd,J=2.4,8.2Hz,3H).LC-MS=378.4[M+H] + .

[0210] Example 11-0: 8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-oxa-8-azaspiro[4.5]decan-4-amine [ka] Compound 11-0 was prepared in the following manner. [ka] To a solution of methyl piperidine-4-carboxylate (10.0 g, 69.84 mmol) in DCM (200 mL) was added (Boc)O (24.07 mL, 104.76 mmol) and EtN (19.63 mL, 139.68 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (100 mL) and washed with HO (50 mL) and brine (50 mL). The organic layer was dried over NaSO and concentrated in vacuo to give 16.5 g of compound 11-1 as a light brown liquid, which was used in the next step without further purification. 1H NMR(400MHz,DMSO-d6)δ 3.83(dt,J=13.2,3.9Hz,2H),3.61(s,3H),2.81(d,J=14.0Hz,2H),2.54(dt,J=1 1.1,3.9Hz,1H),1.84-1.73(m,2H),1.44-1.32(m,11H).LC-MS=144.2[M+H-Boc] + , retention time = 1.24 min (Method N).

[0211] [ka] To a solution of oxalyl dichloride (13.37 mL, 155.96 mmol) in DCM (500 mL), anhydrous DMSO (24.17 mL, 340.27 mmol) was added dropwise at −78 °C, and the mixture was stirred at −78 °C for 30 min. A solution of 2-((tert-butyldimethylsilyl)oxy)ethan-1-ol Compound 11-2 (25.0 g, 141.78 mmol) in DCM (100 mL) was added to the mixture at −78 °C and stirred for 30 min. EtN (98.81 mL, 708.89 mmol) was added, and the reaction was stirred at −78 °C for an additional 1 h. The reaction mixture was acidified to pH = 4 with 2 N aqueous HCl and extracted with DCM (3 × 300 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to give 24.5 g of compound 11-3 as an oil, which was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ 9.69(d,J=1.0Hz,1H),4.20(d,J=0.9Hz,2H),0.91(s,9H),0.09(s,6H).

[0212] [ka] To a solution of compound 11-1 (6.3 g, 25.89 mmol) in anhydrous THF (70 mL), 1.0 M LiHMDS (31.07 mL, 31.07 mmol) was added dropwise at −78° C., and the mixture was stirred at 0° C. for 1 h. The resulting orange solution was recooled to −78° C., and a solution of compound 11-3 (7.49 g, 42.98 mmol) in anhydrous THF (30 mL) was added. The mixture was stirred at the same temperature for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with Et2O (3 × 100 mL). The combined organic layers were washed with HO (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give 6.3 g of compound 11-4 as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ 5.11-4.99(m,1H),3.90-3.78(m,2H),3.62(s,3H),3.56-3.39(m,3H),1.90-1.75(m,2 H),1.68-1.42(m,2H),1.38(s,9H),0.85(s,9H),0.01(s,6H).LC-MS=318.2[M+H-Boc] + , retention time = 1.539 minutes.

[0213] [ka] To a solution of compound 11-4 (21.5 g, 51.48 mmol) in anhydrous THF (150 mL), LiBH (4.49 g, 205.93 mmol) was added portionwise at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was cooled to 0 °C, and saturated aqueous NaHCO:H O (1:2, 50 mL) was added, and the resulting mixture was stirred until bubbling subsided. The mixture was diluted with EtOAc (200 mL), and the mixture was filtered. The organic layer was separated, and the aqueous layer was extracted with EtOAc (3 × 75 mL). The combined organic layers were washed with brine (50 mL), dried over Na SO , and concentrated in vacuo to give 20.0 g of compound 11-5 as a solid. 1H NMR(400MHz,DMSO-d6)δ 4.63-4.51(m,1H),4.48-4.36(m,2H),4.15-3.93(m,1H),3.82-3.36(m,6H), 1.54-1.30(m,12H),0.86(s,9H),0.05--0.00(m,6H).LC-MS=290.2[M+H-Boc] + , retention time = 1.412 min.

[0214] [ka] To a solution of compound 11-5 (20.0 g, 51.33 mmol) in anhydrous THF (200 mL), 1.0 M TBAF in THF (77 mL, 77.0 mmol) was added dropwise at room temperature, and the reaction mixture was stirred for 1 hour. The reaction mixture was treated with saturated aqueous NaHCO3:HO (1:2, 60 mL), and the layers were separated. The aqueous layer was extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo to give 9.6 g of compound 11-6 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 4.56(t,J=5.1,5.1Hz,1H),4.46(t,J=4.8,4.8Hz,2H),4.12-4.03(m,1H),3.59-3.45(m,2H),3.42(d ,J=5.2Hz,2H),3.40-3.32(m,2H),3.17(d,J=5.3Hz,2H),1.52-1.25(m,13H).LC-MS=176.2[M+H-Boc] + , retention time = 1.04 min.

[0215] [ka] To a suspension of 60% NaH (4.88 g, 122.03 mmol) in anhydrous THF (100 mL) was added a solution of compound 11-6 (9.6 g, 34.87 mmol) in anhydrous THF (60 mL), followed by a solution of TsCl (6.65 g, 34.87 mmol) in anhydrous THF (40 mL) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NH Cl solution at -20 °C and stirred until bubbling ceased. The aqueous layer was then extracted with EtOAc (3 × 150 mL). The combined organic layers were washed with brine (50 mL), dried over Na SO , and concentrated in vacuo to give 5.0 g of compound 11-7 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 4.93(d,J=4.8Hz,1H),4.67(t,J=5.3Hz,1H),3.51-3.41(m,4H),3.39-3. 34(m,2H),2.90-2.63(m,3H),1.54-1.20(m,13H).LC-MS=158.2[M+H-Boc] + , retention time = 1.11 min.

[0216] [ka] To a solution of compound 11-7 (5.0 g, 19.43 mmol) in DCM (100 mL) was added DMP (12.36 g, 29.15 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was quenched with saturated NaSO (100 mL) at 0 °C, and then the organic layer was separated. The aqueous layer was extracted with DCM (3 × 100 mL). The combined organic layers were washed with saturated NaHCO solution (50 mL), HO (50 mL), and brine (50 mL), dried over NaSO, concentrated in vacuo, and purified by normal phase chromatography using a running gradient of 10% EtOAc / hexane to give 3.8 g of compound 11-8 as a solid. LC-MS = 156.15 [M+H-Boc] + , retention time = 1.20 min (method O).

[0217] [ka] To a solution of compound 11-8 (3.8 g, 14.88 mmol) in THF (80 mL) was added Ti(OEt) (12.57 mL, 59.53 mmol) and 2-methylpropane-2-sulfinamide (2.71 g, 22.33 mmol) at room temperature. The reaction mixture was heated at 90 °C for 1 h. The reaction mixture was cooled to 0 °C, and LiBH (0.402 g, 18.46 mmol) was added. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was quenched with MeOH and then concentrated in vacuo. The resulting residue was diluted with brine and extracted with EtOAc (4 × 100 mL). The combined organic layers were dried over Na SO , concentrated in vacuo, and purified by normal-phase chromatography using a running gradient of 2% MeOH / DCM to give 1.5 g of compound 11-9 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 5.32-5.27(m,1H),3.99-3.91(m,1H),3.88-3.69(m,3H),3.60(d,J=8.8Hz,1H),3.50-3.42(m,2H ),2.91-2.64(m,2H),1.71-1.51(m,2H),1.40(d,J=3.2Hz,11H),1.14-1.08(m,9H).LC-MS=261.2 [M+H-Boc] + , retention time = 1.175 min.

[0218] [ka] To a solution of compound 11-9 (1.5 g, 4.16 mmol) in MeOH (10 mL) was added 4 M HCl in dioxane (10.4 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The crude material was triturated with EtO (2 × 20 mL), filtered off, and dried to give 1.0 g of compound 11-10 as a solid. LC-MS = 157.2 [M+H] + , retention time = 0.295 min.

[0219] [ka] To a solution of compound 11-10 (1.0 g, 4.36 mmol) in MeCN (10 mL) was added compound 1 (1.44 g, 4.36 mmol) and DIPEA (6.08 mL, 34.91 mmol) at room temperature. The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography using a running gradient of 1-2% MeOH / DCM to give 0.80 g of compound 11-11 as a solid. LC-MS = 405.9 [M+H] + , retention time = 1.039 min.

[0220] [ka] To a suspension of KPO (0.628 g, 2.96 mmol) in dioxane was added HO (1:1) (10 mL, compound 11-11 (0.8 g, 0.98 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (0.251 g, 1.48 mmol), and PdCl(dppf)-DCM complex (0.080 g, 0.098 mmol) at room temperature. The reaction mixture was heated at 80 °C for 1 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with HO (10 mL). The aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with brine (10 mL). The organic layer was dried over NaSO, concentrated in vacuo, and purified by normal-phase chromatography using a running gradient of 1–2% MeOH / DCM to give 0.24 g of compound 11 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 8.19(dd,J=8.7,6.8Hz,1H),7.48(s,1H),7.05(dd,J=11.4,2.6Hz,1H),6.91(td,J=8.4,2.5Hz,1H),3.98(dd,J=8.9,6.5Hz,1H),3.90(s ,2H),3.78-3.60(m,4H),3.39-3.33(m,3H),3.20-3.11(m,1H),1.88-1.62(m,2H),1.58-1.43(m,2H).HPLC: 76.50%, retention time = 5.249 min (Method W). LC-MS=404.0[M+H] + , retention time = 1.06 min.

[0221] Compound 12-0: 3-amino-1-(9-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1,4,9-triazaspiro[5.5]undecan-4-yl)-3-methylbutan-1-one [ka] Compound 12-0 was prepared in the following manner. [ka] A mixture of compound 1 (194 mg, 0.588 mmol) and 1,4,9-triazaspiro[5.5]undecan-3-one (150 mg, 0.619 mmol) in EtOH (3 mL) was stirred at 100 °C for 18 h. The reaction was concentrated in vacuo and purified by normal phase chromatography (4 g column) using a running gradient of 0-20% MeOH / DCM to give the expected product, which precipitated upon addition of MeCN. The solid was washed with MeCN to give 242 mg of compound 12-1 as a solid. LC-MS = 419.2 [M+H] + .

[0222] [ka] A mixture of compound 12-1 (70 mg, 0.167 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (37.0 mg, 0.218 mmol), and Na2CO3 (2 M, 586 μL, 1.172 mmol) was suspended in dioxane (837 μL). The mixture was flushed with N2, and PdCl2(Ph3P)2 (5.87 mg, 8.37 μmol) was added. The reaction was heated to 100 °C for 1 h. The mixture was quenched with H2O, followed by the addition of EtOAc. The product precipitated in the organic layer, which was filtered and washed with H2O. The resulting solid was dried, then triturated with MeCN and filtered to give 39 mg of compound 12-2 as a solid. LC-MS = 417.4 [M+H]+ .

[0223] [ka] To a suspension of compound 12-2 (39 mg, 0.094 mmol) in anhydrous THF (468 μL) was added borane tetrahydrofuran complex (281 μL, 0.281 mmol) dropwise at 0° C. The reaction was allowed to warm to room temperature, forming a clear solution. After 2 h, borane tetrahydrofuran complex (281 μL, 0.281 mmol) was added at 0° C. The reaction was allowed to warm to room temperature and stirred for 18 h. The resulting solution was quenched with 1 M HCl at 0° C. Saturated NaHCO3 solution was then added to adjust the pH to neutral. EtOAc was then added. The organic layer was then separated, washed with brine, dried over MgSO4, filtered, and evaporated. The resulting crude material was purified by preparative HPLC to give 8.4 mg of compound 12-3. LC-MS=403.4 [M+H] + .

[0224] [ka] To a solution of compound 12-3 (8.4 mg, 0.021 mmol) in DMF (1 mL) was added 3-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (5.44 mg, 0.025 mmol), HATU (11.90 mg, 0.031 mmol), and EtN (8.68 μL, 0.063 mmol). The reaction mixture was stirred for 3 h. The mixture was quenched with saturated NH4Cl solution, dried over MgSO4, filtered, and concentrated in vacuo to give a solid. The resulting product was then dissolved in MeOH (1 mL), followed by the addition of 4 M HCl (300 μL, 1.200 mmol). The reaction was stirred for 2 days. The resulting solution was concentrated in vacuo and purified by preparative HPLC to give 3.7 mg of compound 12. 1H NMR(500MHz,MeOD-d4)δ 8.23(dd,J=8.8,6.5Hz,1H),7.81(s,1H),6.98(dd,J=11.0,2.5Hz,1H),6.83(td,J=8.4,2.5Hz,1H),4.03(s,2H),3.95(s,5H),3.89-3.84(m,2 H),3.62-3.53(m,2H),3.40(t,J=5.5Hz,2H),2.90(s,2H),2.16(d,J=13.8Hz,2H),2.07-1.98(m,2H),1.43(d,J=8.1Hz,6H).LC-MS=502.2[M+H] + .

[0225] The following compounds were prepared by the same route used to prepare compound 12-0 using the appropriate starting materials.

[0226] [Table 32]

[0227] Example 13-0: 1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-(morpholinomethyl)piperidin-4-amine [ka] Compound 13-0 was prepared in the following manner. [ka] A mixture of compound 1 (480 mg, 1.455 mmol), tert-butyl (4-(hydroxymethyl)piperidin-4-yl)carbamate acetate (507 mg, 1.746 mmol), compound 2b, and EtN (0.6 mL, 4.3 mmol) in dioxane (10 mL) was heated to 80° C. for 8 hours. The mixture was concentrated in vacuo, then redissolved in DCM and washed with 0.1 M HCl. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with saturated aqueous NaHCO, dried over NaSO, and concentrated in vacuo to give 511 mg of compound 13-1 as a solid. LC-MS=480.1 [M+H] + .

[0228] [ka] Compound 13-1 (400 mg, 0.834 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (184 mg, 1.085 mmol), and Na2CO3 (2 M, 2921 μL, 5.84 mmol) were suspended in dioxane (4172 μL). The mixture was then flushed with N2, and PdCl2(Ph3P)2 (29.3 mg, 0.042 mmol) was added. The reaction was heated to 100 °C for 2 h. The mixture was diluted with EtOAc and H2O. The organic layer was separated, washed with H2O, dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with MeCN, filtered, and washed with MeCN to give 310 mg of compound 13-2 as a solid. 1 H NMR(500MHz,DMSO-d6)δ 8.22(dd,J=8.7,6.8Hz,1H),7.48(s,1H),7.06(dd,J=11.4,2.6Hz,1H),6.92(td, J=8.5,2.6Hz,1H),6.55(d,J=25.3Hz,1H),4.78(t,J=5.7Hz,1H),3.91(s,3H),3. 64(d,J=13.0Hz,2H),3.44(d,J=5.7Hz,2H),3.31-3.25(m,2H),2.14(d,J=14.0Hz ,1H),2.08(s,10H),1.63(td,J=13.0,4.6Hz,2H),1.39(s,8H).LC-MS=478.1[M+H]+ .

[0229] [ka] To a mixture of compound 13-2 (150 mg, 0.314 mmol) in DCM (4986 μL) was added DMP (266 mg, 0.628 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into H2O and extracted twice with EtOAc. The combined organic layers were dried over MgSO4 and concentrated in vacuo to give 123 mg of compound 13-3. LC-MS = 476.3 [M+H] + .

[0230] [ka] To a solution of compound 13-3 (70 mg, 0.074 mmol), morpholine (19.2 mg, 0.221 mmol), sodium acetate (36.2 mg, 0.442 mmol), and AcOH (25.3 μL, 0.442 mmol) in DCM was added NaBH(OAc) (94 mg, 0.442 mmol). The resulting cloudy mixture was stirred at room temperature for 2 h. Saturated NaHCO solution was added to the reaction mixture at 0 °C and stirred for 5 min. The mixture was extracted twice with DCM. The combined organic layers were washed once with brine, filtered, dried over MgSO, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (4 g column) using a running gradient of 0–100% EtOAc / cyclohexane followed by 0–10% MeOH / DCM to give compound 13-4. LC-MS = 547.4 [M+H] + .

[0231] [ka] Compound 13-4 (30 mg, 0.055 mmol) was dissolved in MeOH (274 μL), and then 4 M HCl (233 μL, 0.933 mmol) was added. The reaction was stirred at room temperature for 2 hours. The resulting solution was concentrated in vacuo and purified by preparative HPLC to give 5.1 mg of compound 13 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 8.18(dd,J=8.7,6.8Hz,1H),7.88(s,3H),7.52(s,1H),7.08(dd,J=11.4,2.5Hz,1H),6.90(td,J=8.5,2.5Hz,1H),3.91(s,4H),3.69(d d,J=14.1,5.3Hz,3H),3.62(t,J=4.4Hz,4H),3.59-3.45(m,3H),2.65(s,2H),2.59-2.54(m,3H),1.97-1.77(m,4H).LC-MS=447.4[M+H] + .

[0232] Example 14-0: 7-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-amine [ka] Compound 14-0 was prepared in the following manner. [ka] To a solution of 7-benzyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine in THF at -78 °C was added n-BuLi (2.5 M, 0.7 mL). After 0.5 h, a solution of 4-methylbenzenesulfonyl azide (30 wt. / wt. PhMe) in THF (0.5 mL) was added. The reaction mixture was stirred at -78 °C for 10 min and then allowed to stand at room temperature for 20 min. The reaction was quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc, and the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by normal-phase chromatography using a running gradient of 0-50% EtOAc / cyclohexane to give 289 mg of compound 14-1. LC-MS = 255.4 [M+H] + .

[0233] [ka] A mixture of compound 14-1 and Pd(OH) on carbon in EtOH was stirred under H at room temperature for 13 hours. 3M HCl (0.1 mL) was then added. The reaction mixture was stirred under H at room temperature for 2 hours. The mixture was filtered through an HPLC filter and washed with MeOH. The filtrate was concentrated in vacuo to give 57.8 mg of compound 14-2. 1 H NMR(500MHz,MeOD-d4)δ 6.63(d,J=1.7Hz,1H),3.94(d,J=1.6Hz,2H),3.76(t,J=5.8Hz,2H),3.33(m,J =1.6Hz,2H),3.26(t,J=5.8Hz,2H),1.20(t,J=7.1Hz,1H).LC-MS=139.4[M+H] + .

[0234] The following compound 14-0 was prepared by the same route used to prepare compound 4-0.

[0235] [Table 33]

[0236] Example 15-0: (1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-((oxetan-3-ylmethyl)amino)piperidin-4-yl)methanol [ka] Compound 15-0 was prepared from compound 4-98, followed by reductive amination.

[0237] [ka] To a solution of compound 4-98 (50 mg, 0.121 mmol) in anhydrous DCM (604 μL), sodium acetate (59.5 mg, 0.725 mmol), and AcOH (41.5 μL, 0.725 mmol) was added oxetane-3-carbaldehyde (24.76 μL, 0.362 mmol) and NaBH(OAc) (154 mg, 0.725 mmol). The reaction was stirred at room temperature for 1 h. Saturated NaHCO solution was added to the reaction mixture at 0 °C and stirred for 5 min. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, filtered, dried over MgSO, and concentrated in vacuo. The crude material was purified by normal phase chromatography (4 g) using a running gradient of 0–10% MeOH / DCM to give 29 mg of compound 15-0 as a white foam. 1 H NMR(500MHz,DMSO-d6)δ 8.20(dd,J=8.7,6.8Hz,1H),7.47(s,1H),7.06(dd,J=11.4,2.5Hz,1H),6.91(td,J=8.5,2.6Hz,1H),4.64(dd,J=7.7,5.8Hz,3H),4.28(t,J= 5.9Hz,2H),3.91(s,3H),3.59-3.42(m,4H),3.30(s,2H),3.02-2.88(m,1H),2.74(m,2H),1.59(dd,J=35.0,13.1Hz,4H).LC-MS=448.3[M+H] + .

[0238] The following compounds were prepared by the same route used to prepare compound 15-0 using the appropriate starting materials.

[0239] [Table 34]

[0240] Example 16-0: (4-((3-aminopropyl)amino)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)methanol [ka] Compound 16-0 was prepared from compound 4-98, followed by reductive amination and Boc deprotection.

[0241] [ka] To a solution of compound 4-98 (50 mg, 0.121 mmol) in anhydrous DCM (1.5 mL), sodium acetate (59.5 mg, 0.725 mmol), and AcOH (0.041 mL, 0.725 mmol) was added tert-butyl (3-oxopropyl)carbamate (0.062 mL, 0.362 mmol) and NaBH(OAc) (154 mg, 0.725 mmol). The reaction mixture was stirred at room temperature for 1 h. Saturated NaHCO solution was added to the reaction mixture at 0 °C and stirred for 5 min. The aqueous layer was extracted twice with DCM. The combined organic layers were washed with brine, filtered, dried over MgSO, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (4 g) using a running gradient of DCM / MeOH 0-10% to give 28 mg of compound 16-1 as a white foam. LC-MS=535.4[M+H] + .

[0242] [ka] To a solution of compound 16-1 (27 mg, 0.051 mmol) in anhydrous dioxane (300 μL) was added 4 M HCl in dioxane (101 μL, 0.404 mmol). The resulting white suspension was stirred at room temperature for 40 minutes. The resulting white suspension was concentrated in vacuo and then triturated with MeCN. The white suspension was filtered and dried to give compound 16 as a white powder. 1 H NMR(500MHz,MeOD-d4)δ 8.28(dd,J=8.7,6.5Hz,1H),7.89(s,1H),7.05(dd,J=11.0,2.5Hz,1H),6.89(td,J=8.4,2.5Hz,1H),4.04(d,J=13.8Hz,1H),3.99(s,3H) ,3.96(s,2H),3.61-3.48(m,2H),3.26-3.19(m,2H),3.11(t,J=7.7Hz,2H),2.23(d,J=13.5Hz,3H),2.20-2.09(m,3H).LC-MS=435.4[M+H] + .

[0243] Compound 17-0: 6-(aminomethyl)-2-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2-azaspiro[3.3]heptan-6-ol Compound 17-0 was prepared in the following manner. [ka] To a solution of tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate (3 g, 14.198 mmol) in THF (30 mL) at −78 °C, vinylmagnesium bromide (1.0 M in THF, 17 mL, 17.037 mmol) was added dropwise and stirred at −78 °C for 30 min. The reaction mixture was quenched with saturated NH₄Cl. The layers were separated, the aqueous layer was extracted with DCM, and the combined organic layers were dried over Na₂SO₄ and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 50–60% EtOAc / hexanes to give 1.15 g of compound 17-1 as a solid. 1H NMR(600MHz,CDCl3)δ 5.99(dd,J=17.3,10.6Hz,1H),5.24(d,J=17.2Hz,1H),5.10(d,J=10.6Hz,1H),3.94(s,2H),3. 87(s,2H),2.51-2.40(m,2H),2.37-2.27(m,2H),1.80(s,1H),1.42(s,9H).LC-MS=240.25[M+H] + , retention time = 1.46 min.

[0244] [ka] A stirred solution of compound 17-1 (700 mg, 2.924 mmol) in 10% MeOH in DCM (20 mL) at −78° C. was purged with ozone for 40 min, followed by purging with N2 to remove excess ozone. After purging with N2 for 10 min, dimethyl sulfide (1.81 g, 29.249 mmol) was added dropwise at −78° C. and allowed to warm to room temperature for 30 min. The reaction mixture was quenched with saturated NH4Cl. The layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4 and concentrated in vacuo at 30° C. to give 700 mg of compound 17-2 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 4.05-3.83(m,4H),2.78-2.65(m,1H),2.60-2.44(m,2H),2.31-2.12(m,1H),1.43(s,9H).

[0245] [ka] To a solution of compound 17-2 (300 mg, 1.243 mmol) in dichloroethane (4 mL) was added benzylamine (133 mg, 1.243 mmol) at 0 °C. Then, NaBH(OAc) (395 mg, 1.865 mmol) was added portionwise at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NH Cl. Both layers were separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na SO and concentrated in vacuo at 30 °C. The crude material was purified by normal phase chromatography using a running gradient of 8-10% MeOH / DCM to give 150 mg of compound 17-3 as a yellow sticky mass. LC-MS = 333.20 [M+H] + , retention time = 1.32 min.

[0246] [ka] To a solution of compound 17-3 (150 mg, 0.451 mmol) in MeOH (4 mL), 10% Pd / C (100 mg) was added under H2 at room temperature and stirred for 5 h at room temperature while maintaining H2 pressure. The reaction mixture was filtered through a CELITE pad, the CELITE pad was washed with MeOH, and the filtrate was concentrated in vacuo to give 100 mg of compound 17-4 as a colorless sticky mass. 1 H NMR(600MHz,CDCl3)δ 3.91(s,2H),3.88(s,2H)2.69(s,2H),2.33-2.13(m,4H)1.42(s,9H).LC-MS=284.15[M+42] + (MeCN adduct), retention time = 1.23 min.

[0247] [ka] To a solution of compound 17-4 (170 mg, 0.702 mmol) in DCM (10 mL) was added DIPEA (109 mg, 0.842 mmol) at 0 °C. After 15 min, Fmoc chloride (199 mg, 0.772 mmol) was added dropwise at 0 °C. The reaction was then allowed to reach room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 6–8% MeOH / DCM to give 280 mg of compound 17-5 as a solid. 1 H NMR(300MHz,CDCl3)δ 7.77(d,J=7.5Hz,2H),7.59(d,J=7.3Hz,2H),7.46-7.37(m,2H),7.35-7.28(m,2H),4.45(d,J=6.7Hz,2H),4.21( t,6.6Hz,1H),3.92(d,J=7.8Hz,4H),3.22(d,J=6.1Hz,2H),2.40-2.06(m,4H),1.42(s,9H).LC-MS=465.25[M+H] + Retention time = 1.57 minutes.

[0248] [ka] To a solution of compound 17-5 (280 mg, 0.603 mmol) in DCM (3 mL) was added TFA (1 mL) dropwise at 0 °C, and then the reaction mixture was allowed to reach room temperature over 1 h. The reaction mixture was concentrated in vacuo at 30 °C. The crude material was triturated with pentane to give 300 mg of compound 17-6 as a colorless sticky mass. 1 H NMR(300MHz,CDCl3)δ 8.41(s,1H),7.77(d,J=7.5Hz,2H),7.56(d,J=7.5Hz,2H),7.41(t,J=7.4Hz,2H),7.37-7.27(m ,2H),4.46(d,J=6.5Hz,2H),4.19(s,5H),3.18(s,1H),2.52-2.21(m,4H).LC-MS=365.20[M+H] + , retention time = 1.31 min.

[0249] [ka] A mixture of compound 17-6 (300 mg, 0.627 mmol), compound 1 (207 mg, 0.627 mmol), and DIPEA (86 mg, 3.762 mmol) in MeCN (4 mL) was heated at 100° C. for 90 min in a microwave oven. The reaction mixture was allowed to reach room temperature for 1 h until a precipitate formed. The solid was filtered and washed with MeCN and pentane. The solid was dried to give compound 17-7, which was used directly in the next step. LC-MS=614.10 [M+H] + , retention time = 1.55 min.

[0250] [ka] To a solution of compound 17-7 (120 mg, 0.196 mmol) in 4:1 dioxane / HO (4 mL / 1 mL) was added KPO (104 mg, 0.489 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (67 mg, 0.391 mmol), and PdCl(dppf)-DCM complex (16 mg, 0.019 mmol). The reaction mixture was heated at 100 °C for 6 h, after which it was diluted with HO and extracted with EtOAc (2 times). The combined organic layers were washed with HO, brine, dried over NaSO, filtered, and concentrated in vacuo to give the crude material, which was purified by normal-phase chromatography using a running gradient of 8–10% MeOH / DCM to give compound 17-8 as a solid. 1H NMR (600 MHz, CDCl3) δ 8.17(dd,J=8.6,6.7Hz,1H),7.77(d,J=7.6Hz,2H),7.59(d,J=7.6Hz,3H),7.41 (t,J=7.5,7.5Hz,2H),7.32(t,J=7.5,7.5Hz,2H),6.79-6.68(m,2H),5.19(d,J =6.3Hz,1H),4.48(d,J=6.7Hz,2H),4.27-4.11(m,4H),3.90(s,3H),3.27(d,J= 6.2Hz,2H),2.28(d,J=12.8Hz,2H),2.44(d,J=12.8Hz,2H).LC-MS=612.10[M+H] + , retention time = 1.59 min.

[0251] [ka] To a solution of compound 17-8 (90 mg, 0.147 mmol) in DCM (2.0 mL) was added piperidine (0.1 mL) at 0 °C. The reaction was then stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo. The crude material was triturated with EtO. The resulting mixture was purified by preparative HPLC (Method M) to give 23 mg of compound 17 as a solid. 1 H NMR(400MHz,MeOD-d4)δ 8.26(dd,J=8.8,6.5Hz,1H),7.90(d,J=17.3Hz,1H),7.03(dd,J=11.0,2.5Hz,1H),6.86(td,J= 8.5,2.5Hz,1H),4.33(s,4H),3.97(s,3H),3.00(s,2H),2.64-2.41(m,4H).LC-MS=390.05[M+H] + , retention time = 1.29 min.

[0252] Implementation 18-0 (single enantiomer): 3-(aminomethyl)-1-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)pyrrolidin-3-ol [ka] Compound 18-0 was prepared in the following manner. [ka] To a suspension of NaH (60% in mineral oil, 1.78 g, 44.51 mmol) in DMSO (40 mL) at 10 °C, trimethylsulfoxonium iodide (8.31 g, 37.66 mmol) was added portionwise, and the reaction was stirred at room temperature for 1 h. A solution of 1-benzylpyrrolidin-3-one (6 g, 34.24 mmol) in DMSO (30 mL) was added, and the reaction was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 50–100% EtOAc / hexane to give 3.0 g of compound 18-1 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.38-7.21(m,5H),3.72-3.58(m,2H),2.85(d,J=0.8Hz,2H),2.82-2.77(m,2H),2.69(ddd,J=9.1,7.6,5.5Hz,1 H),2.59(d,J=10.7Hz,1H),2.20(dt,J=14.2,7.2Hz,1H),1.92(ddd,J=13.6,7.6,5.5Hz,1H).LC-MS=190.1[M+H] + , retention times = 0.13 min and 0.28 min (Method 12).

[0253] [ka] To a solution of compound 18-1 (3.0 g, 15.85 mmol) in MeOH (18 mL) at 0 °C, 28% aqueous NH (36 mL) was added dropwise and stirred at room temperature for 16 h. The reaction mixture was diluted with DCM, washed with 1 N NaOH solution, HO, brine, dried over NaSO, and concentrated in vacuo to give compound 18-2. 1H NMR(600MHz,CDCl3)δ 7.37-7.20(m,5H),3.62(d,J=2.7Hz,2H),2.83(q,J=7.7Hz,1H),2.77(s,2H),2.60(d,J=9.8H z,1H),2.47(q,J=7.9Hz,1H),2.41(d,J=9.6Hz,1H),1.83(t,J=7.3Hz,2H).LC-MS=206.9[M+H] + , retention time = 0.27 min (Method Q).

[0254] [ka] To a solution of compound 18-2 (2.60 g, 12.60 mmol) in DCM (25 mL) at 0 °C, (Boc)2O (3.30 g, 15.12 mmol) was added dropwise and stirred at room temperature for 2 h. The reaction mixture was concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 5-10% MeOH / DCM to give 1.75 g of compound 18-3 as a solid. 1 H NMR(300MHz,CDCl3)δ 7.40-7.13(m,5H),3.61(d,J=1.8Hz,2H),3.27(d,J=5.9Hz,2H),3.03-2.74(m,1H),2.62(d,J =9.7Hz,1H),2.43(td,J=9.5,6.0Hz,2H),2.09-1.71(m,2H),1.43(s,9H).LC-MS=307.1[M+H] + , retention time = 1.29 min (method 12).

[0255] [ka] Chiral separation of racemic compound 18-3 (700 mg) using chiral purification method (Method 14) gave compound 1-4 peak 1 (300 mg) as a solid. LC-MS = 307.5 [M+H] +, retention time = 0.11 min. HPLC: 97.55%, retention time = 5.17 min (Method 14). Chiral HPLC 98.26%, retention time = 7.97 min, compound 1-4 peak-2 (240 mg) as a solid. LC-MS = 307.5 [M+H] + , retention time = 0.12 min. Chiral HPLC: 98.23%, retention time = 9.47 min.

[0256] [ka] To a solution of compound 18-4 peak 1 (300 mg, 0.979 mmol) in MeOH (10 mL) was added 10% Pd / C (100 mg) and HCOONH (374 mg, 5.874). The reaction was heated to 70 °C for 3 h. The reaction mixture was cooled to room temperature and filtered through a CELITE pad, and the CELITE pad was washed with MeOH. The resulting filtrate was concentrated in vacuo to give 210 mg of compound 18-5 as a colorless sticky mass. 1 H NMR(400MHz,DMSO-d6)δ 6.64(t,J=6.1Hz,1H),4.56(s,1H),3.17(d,J=1.8Hz,2H),3.05(d,J=6.0Hz,2H),2.86(dt,J=10.6,7.7Hz,1H), 2.69(ddd,J=10.3,8.2,4.4Hz,1H),2.61(d,J=11.5Hz,1H),1.69-1.42(m,2H),1.38(s,9H).LC-MS=217.0[M+H] + , retention time = 0.33 min (method 12).

[0257] The following compounds were prepared by the same route used to prepare compound 4-0 using the appropriate starting materials.

[0258] [Table 35]

[0259] Example 19-0: 4-amino-1-(5-(2-methoxy-4-methylphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol [ka] Compound 19-0 was prepared in the following manner. [ka] To a solution of 4-methylpyridine (1-1, 20 g, 214.7 mmol) in MeCN (200 mL) was added BnBr (28 mL, 236.2 mmol) at 0 °C. The resulting solution was stirred at 70 °C for 3 h. The reaction was cooled to room temperature and concentrated in vacuo to give 55 g of compound 19-2 as a solid, which was used in the next step without further purification. 1 H NMR(300MHz,DMSO-d6)δ 9.08(d,J=6.3Hz,2H),8.03(d,J=6.3Hz,2H),7.57-7.42(m,5H),5.81(s,2H),2.63(s,3H).

[0260] [ka] A solution of compound 19-2 (55 g, 208.2 mmol) in MeOH (100 mL) was cooled to 0 °C, and NaBH (16 g, 416.4 mmol) was added portionwise at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction was concentrated in vacuo, iced HO was added, and then extracted with EtOAc (3 × 100 mL). The combined organic layers were washed with HO, brine, then dried over NaSO, filtered, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography (40.0 g neutral alumina column) using a running gradient of 0–20% EtOAc / hexane to give 27 g of compound 19-3 as an oil. 1H NMR(300MHz,CDCl3)δ 7.44-7.17(m,5H),5.37(bs,1H),3.57(s,2H),2.98-2.90(m,2H),2.56(t,J=5.8Hz,2H),2.14-2.03(m,2H),1.68(s,3H).LC-MS=188.2[M+H] + , retention time = 0.146 min.

[0261] [ka] To a solution of compound 19-3 (27 g, 72.14 mmol) in IPA:HO (204.5 mL, 1:2), TFA (5.5 mL, 72.14 mmol) was added dropwise over 5 min at 0 °C, followed by the portionwise addition of NBS (16.7 g, 93.8 mmol) at the same temperature. The reaction was stirred at room temperature and then heated to 50 °C for 16 h. The reaction was cooled to room temperature, and 20% aqueous NaOH (120 mL) was added. The resulting mixture was stirred at room temperature for 6 h, then concentrated in vacuo, diluted with HO, and extracted twice with EtO (100 mL). The combined organic layers were washed with HO, brine, dried over NaSO, filtered, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography (80 g column) using a running gradient of 0–50% EtOAc / n-hexane to give 18 g of compound 19-4 as an oil. 1 H NMR(600MHz,CDCl3)δ 7.38-7.14(m,5H),3.52-3.34(m,2H),3.14-2.97(m,2H),2.57(d,J=13.3Hz,1H),2.4 3-2.27(m,1H),2.15-2.10(m,1H),1.92-1.86(m,2H),1.34(s,3H).LC-MS=204.1[M+H] + , retention time = 0.134 min.

[0262] [ka] To a solution of compound 19-4 (9 g, 44.27 mmol) in HO (119 mL) was added AcOH (58 mL) at 0 °C, followed by the portionwise addition of NaN (14.4 g, 221.4 mmol) at the same temperature. The reaction was stirred at room temperature for 24 h, quenched with saturated NaHCO solution, and extracted twice with EtOAc (100 mL). The combined organic layers were washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo. One more 9 g batch was repeated, and the resulting crude material was combined and purified by normal-phase chromatography (80 g column) using a running gradient of 20–30% EtOAc / n-hexane to give 11.7 g of compound 19-5 as an oil. 1 H NMR(300MHz,CDCl3)δ 7.41-7.18(m,5H),3.53(s,2H),3.36(s,1H),3.00(d,J=9.2Hz,1H),2.73-2.47(m,3H),2.30( td,J=11.4,3.2Hz,1H),1.90-1.78(m,1H),1.63-1.55(m,1H),1.39(s,3H).LC-MS=247.1[M+H] + , retention time = 0.27 min.

[0263] [ka] To a solution of compound 19-5 (6 g, 24.35 mmol) in MeOH (100 mL) was added HCOONH4 (3.07 g, 48.7 mmol), followed by Zn dust (4.77 g, 73.1 mmol) at room temperature. The reaction was stirred at room temperature for 30 min. The reaction was filtered through a pad of CELITE, washed with MeOH (2 x 30 mL), and the resulting filtrate was concentrated in vacuo. Repeated batches were performed on the same scale and combined to give 10.3 g of crude compound 19-6, which was used in the next step without further purification. LC-MS = 221.1 [M+H] + , retention time = 0.131 min.

[0264] [ka] To a solution of compound 19-6 (10.3 g, 46.75 mmol) in dioxane (60 mL) was added Na2CO3 (19.8 g, 187.2 mmol) at 0 °C, followed by (Boc)2O (21.5 mL, 93.5 mmol). The reaction mixture was stirred at room temperature for 16 h, concentrated in vacuo, diluted with EtOAc (200 mL), and then washed with HO. The combined organic layers were washed with HO, brine, then dried over Na2SO4, filtered, and concentrated in vacuo to give the crude compound. The crude compound was purified by normal-phase chromatography (40.0 g column) using a running gradient of 5–10% EtOAc / n-hexane to give 11.8 g of compound 19-7 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 7.39-7.16(m,5H),6.28(s,1H),4.76(s,1H),3.70(s,2H),3.45(q,J=13.2Hz,2H),2.10(t,J=1 0.5Hz,1H),2.04-1.92(m,1H),1.92-1.69(m,2H),1.37(s,9H),1.13(s,3H).LC-MS=321.2[M+H] + , retention time = 1.33 min.

[0265] [ka] 10% Pd / C (6.0 g) was added to an N-degassed solution of compound 19-7 (13 g, 40.57 mmol) in MeOH (200 mL) and stirred under H at room temperature for 4 h. The reaction was filtered through a pad of CELITE, washed with MeOH (2 × 30 mL), and the resulting filtrate was concentrated in vacuo to give 10 g of compound 19-8 as a solid, which was used in the next step without further purification. 1H NMR(600MHz,CDCl3)δ 4.61(s,1H),3.75(dd,J=9.1,4.4Hz,1H),3.07(dd,J=12.5,4.4Hz,1H),2.85(dt,J=12.9,4.5Hz,1H),2.69(ddd ,J=13.2,10.4,3.1Hz,1H),2.59-2.46(m,1H),1.70-1.64(m,1H),1.56-1.49(m,1H),1.44(s,9H),1.36(s,3H).

[0266] The following compounds were prepared by the same route used to prepare compound 4-0.

[0267] [Table 36]

[0268] [Table 37]

[0269] [Table 38]

[0270] Example 20-0: (3S,4S)-3-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-4-ol [ka] Compound 20-0 was prepared in the following manner. [ka] Compound 19-4 (500 mg, 2.46 mmol) was diluted with 30% aqueous ammonia (2 mL), and the reaction was stirred at 60 °C for 20 h. An intermediate was formed. Dioxane (10 mL) was then added, and the mixture was cooled to 0 °C. Na2CO3 (919 mg, 9.35 mmol) was then added, followed by the dropwise addition of (Boc)2O (1.02 g, 4.67 mmol). The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl and extracted twice with DCM (50 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by normal-phase chromatography (12 g column) using a running gradient of 25–30% EtOAc / n-hexane to give 230 mg of compound 20-1 as a solid. 1 H NMR(400MHz,CDCl3)δ 7.37-7.17(m,5H),5.24(s,1H),3.66-3.55(m,1H),3.55-3.37(m,2H),2.72(dd,J=11.2,2.9Hz,1H),2.55-2. 34(m,3H),1.80(bs,1H),1.78-1.69(m,1H),1.62-1.48(m,1H),1.44(s,9H),1.20(s,3H).LC-MS=320.9[M+H] + , retention time = 1.294 min.

[0271] [ka] 10% Pd / C (50 mg) was added to an N-degassed solution of compound 20-1 (160 mg, 0.5 mmol) in MeOH (6 mL). The reaction was stirred under H at room temperature for 4 h. The reaction was filtered through a pad of CELITE, washed with MeOH (2 × 15 mL), and the resulting filtrate was concentrated in vacuo to give 85 mg of crude compound 20-2 as a solid. 1H NMR(300MHz,CDCl3)δ 5.13(s,1H),3.50(d,J=9.4Hz,1H),3.22-3.13(m,2H),3.02-2.86(m,1H),2.76-2.64(m,1H),2.57(dd,J=12 .1,6.5Hz,1H),1.76(ddd,J=13.6,8.2,4.0Hz,2H),1.44(d,J=1.8Hz,9H),1.20(s,3H).LC-MS=230.95[M+H] + , retention time = 0.469 min.

[0272] The following compounds were prepared by the same route used to prepare compound 4-0.

[0273] [Table 39]

[0274] Example 21-0: (3R,4R)-4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-methylpiperidin-3-ol [ka] Compound 21-0 was prepared in the following manner. [ka] To an N2-degassed solution of compound 19-5 (800 mg, 3.25 mmol) in MeOH (5 mL), 10% Pd / C (100 mg) was added and stirred under H2 at room temperature for 16 h. The suspension was filtered through a pad of CELITE and washed twice with MeOH (30 mL). The filtrate was evaporated to give 400 mg of compound 21-1 as a solid. 1H NMR(400MHz,DMSO-d6)δ 4.44(bs,1H),3.32(bs,1H),3.04(dd,J=8.4,4.0Hz,1H),2.77(dd,J=12.5,4.0Hz,1H),2.64(dt,J=12.8,4.7Hz,1H),2.48-2.43 (m,1H),2.28(dd,J=12.5,8.3Hz,1H),1.81-1.50(m,2H),1.46-1.37(m,1H),1.23-1.13(m,1H),0.92(s,3H).LC-MS=131.2[M+H] + , retention time = 0.255 min.

[0275] [ka] Compound 1 (400 mg, 1.21 mmol), compound 21-1 (190 mg, 1.5 mmol), DIPEA (457 mg, 3.63 mmol), and MeCN (5 mL) were heated at 120 °C for 16 h. The reaction was diluted with HO and extracted twice with EtOAc (50 mL). The combined organic layers were washed with brine (50 mL), dried over NaSO, and evaporated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 0 to 17% MeOH / DCM to give 350 mg of compound 21-3 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 7.60(bs,2H),7.10(s,1H),5.87(d,J=4.4Hz,1H),3.80-3.60(m,3H),3.40-3.35( m,1H),3.13(d,J=10.0Hz,1H),1.91-1.75(m,2H),1.27(s,3H).LC-MS=380.0[M+H] + , retention time = 0.97 min.

[0276] [ka] A 2:1:1 DMF / EtOH / HO solution of compound 21-3 (1.0 equiv.), NaCO (3.0 equiv.), and (4-fluoro-2-methoxyphenyl)boronic acid (1.2 equiv.) was degassed with argon for 15 minutes, and then Pd(PPh) (10 mol%) was added. The reaction mixture was heated at 80 °C for 2 hours. It was then diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 0–30% MeOH / DCM to give 12 mg of compound 21 as a solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.19(dd,J=8.8,7.6Hz,1H),7.45(s,1H),7.05(dd,J=11.2,2.4Hz,1H),6.9 1(dt,J=8.0,2.4Hz,1H),5.12(d,J=4.4Hz,1H),3.90(s,3H),3.72(dd,J=12. 8,3.6Hz,1H),3.59-3.51(m,1H),3.49-3.35(m,2H),3.21(dd,J=12.8,6.8Hz ,1H),1.80-1.73(m,1H),1.47-1.39(m,1H),1.09(s,3H).LC-MS=378.1[M+H] + , retention time = 1.09 min.

[0277] Example 22-0: 4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide [ka] Compound 22-0 was prepared in the following manner. [ka] To a suspension of 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl)piperidine-4-carboxylic acid (500 mg, 1.740 mmol), NHCl (186 mg, 3.48 mmol), and HATU (794 mg, 2.088 mmol) in dry THF (10 mL) was added DIPEA (760 μL, 4.35 mmol). The resulting mixture was heated to 60 °C for 2.5 h. The resulting mixture was quenched with saturated NaHCO solution and extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (12 g column) using a running gradient of 0–20% DCM / MeOH to afford 250 mg of compound 22-1 as an oil. 1 H NMR(500MHz,DMSO-d6)δ 7.29(s,1H),7.24(s,1H),3.66(s,3H),3.45-3.38(m,2H),3.19-3.04(m,2H),2.01-1.78(m,4H),1.39(s,9H).

[0278] [ka] To a solution of compound 22-1 (250 mg, 0.611 mmol) in EtOH (3 mL) was added NaBH (69.4 mg, 1.834 mmol). The reaction was stirred at room temperature for 18 h. The mixture was quenched with HO at 0 °C. The resulting cloudy mixture was concentrated in vacuo. The crude material was purified by normal phase chromatography (4 g column) using a 0-100% running gradient to afford 90 mg of compound 22-2 as a white foam. 1 H NMR(500MHz,DMSO-d6)δ 7.30(s,1H),7.24(s,1H),4.81(t,J=5.5Hz,1H),3.63(d,J=13.1Hz,2H),3.37(d,J=5.4Hz, 2H),2.90(s,2H),1.87(d,J=13.7Hz,2H),1.39(s,9H),1.30(ddd,J=14.2,10.8,4.2Hz,2H).

[0279] [ka] To a solution of compound 22-2 (80 mg, 0.310 mmol) in MeOH (666 μL) was added 4 M HCl in dioxane (1316 μL, 5.26 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The resulting white suspension was then concentrated in vacuo and mixed with compound 1 (92 mg, 0.279 mmol) and DIPEA (162 μL, 0.929 mmol) in EtOH (1.3 mL). The reaction mixture was stirred at 90° C. for 3.5 hours. The reaction was concentrated in vacuo to give compound 22-3. LC-MS=408.1 [M+H] + .

[0280] [ka] To a solution of compound 22-3 (126 mg, 0.309 mmol) and (4-fluoro-2-methoxyphenyl)boronic acid (68.4 mg, 0.402 mmol) in dioxane (1.5 mL) was added NaCO 2M (1083 μL, 2.166 mmol) and PdCl(PhP) (10.86 mg, 0.015 mmol) under argon. The reaction mixture was heated to 100 °C for 1 h. The resulting solution was diluted with EtOAc and HO. The aqueous layer was separated, and the organic layer was washed with HO. The resulting organic layer was dried over MgSO 4 , filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (4 g column) using a running gradient of 0–100% DCM / MeOH to afford 73 mg of compound 22-4 as a pale orange foam. 1H NMR(500MHz,DMSO-d6)δ 8.20(ddd,J=8.5,6.8,1.4Hz,1H),7.47(d,J=1.3Hz,1H),7.25(s,1H),7.10-7.01(m,2H),6.92(tt ,J=8.5,1.9Hz,1H),4.93-4.88(m,1H),4.10(tt,J=6.3,3.1Hz,1H),3.91(d,J=1.3Hz,3H),3.68(d t,J=13.1,4.4Hz,2H),3.44(d,J=5.7Hz,2H),3.32(d,J=1.5Hz,2H),3.32-3.21(m,2H),3.18(dd,J =5.2,1.4Hz,2H),2.06(d,J=13.9Hz,2H),1.58(ddd,J=14.6,11.3,4.4Hz,2H).LC-MS=406.1[M+H] + .

[0281] [ka] To a solution of compound 22-4 (32 mg, 0.079 mmol) in DCM (1 mL) was added EtN (0.055 mL, 0.395 mmol), MsCl (0.08 mmol), and DMAP (9.64 mg, 0.079 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. After dilution with EtOAc, the organic layer was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo to give a solid. Next, DMF (1 mL), 15-crown-5 (0.126 mL, 0.631 mmol), and NaN (41.0 mg, 0.631 mmol) were added. The resulting solution was heated to 100 °C for 18 h. After dilution with EtOAc, the organic layer was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo to give 15 mg of compound 22-5. LC-MS=431.3[M+H] + .

[0282] [ka] A solution of compound 22-5 (23 mg, 0.053 mmol) and Ph3P (28.0 mg, 0.107 mmol) in THF (427 μL) was heated at 60° C. for 4 hours. The resulting solution was quenched with aqueous HCl. The resulting mixture was concentrated in vacuo and diluted with THF (1 mL). The reaction was again heated to 60° C. for 18 hours and then to 100° C. for 2 days. The resulting mixture was concentrated in vacuo and purified by preparative HPLC to give 5.8 mg of compound 22. 1 H NMR(500MHz,DMSO-d6)δ 8.20(dd,J=8.7,6.9Hz,1H),7.80(s,2H),7.67(s,1H),7.51(s,1H),7.48(s,1H),7.07(dd, J=11.4,2.6Hz,1H),6.91(td,J=8.4,2.5Hz,1H),3.91(s,3H),3.66-3.60(m,2H),3.40(t,J =9.1Hz,2H),3.07(d,J=6.1Hz,2H),2.19-2.12(m,2H),1.73-1.65(m,2H).LC-MS=405.3[M+H] + .

[0283] Example 23-0: N-((1-aminocyclopropyl)methyl)-4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidine-4-carboxamide [ka] Compound 23-0 was prepared in the following manner. [ka] To a suspension of compound 1 (363 mg, 1.102 mmol) in EtOH (5 mL) was added DIPEA (0.385 mL, 2.203 mmol) and methyl 4-(((tert-butoxycarbonyl)amino)methyl)piperidine-4-carboxylate (300 mg, 1.102 mmol). The resulting suspension was heated at 80 °C for 8 h. The mixture was quenched with saturated NaHCO solution and diluted with EtOAc. The organic layer was separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo to give 460 mg of compound 23-1. LC-MS = 522.1 [M+H] + .

[0284] [ka] To a solution of compound 23-1 (100 mg, 0.192 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (42.4 mg, 0.249 mmol), and NaCO 2M (0.671 mL, 1.343 mmol) in dioxane (2 mL) was added PdCl(PhP) (9.59 μmol). The resulting mixture was heated to 100 °C for 2 h. The mixture was quenched with saturated NaHCO solution and then diluted with EtOAc. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude product was purified by normal-phase chromatography (4 g column) using a running gradient of 0-100% EtOAc / cyclohexane to give 83 mg of compound 23-2 as a solid. LC-MS = 520.0 [M+H] + .

[0285] [ka] To a solution of compound 23-2 (30 mg, 0.058 mmol) in MeOH (462 μL) and HO (115 μL) was added LiOH (2.77 mg, 0.115 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours and then concentrated in vacuo to give compound 23-3. LC-MS=506.2 [M+H]+ .

[0286] [ka] A solution of compound 23-3 (29 mg, 0.057 mmol), tert-butyl (1-(aminomethyl)cyclopropyl)carbamate (14.75 mg, 0.079 mmol), HATU (34.4 mg, 0.091 mmol), and DIPEA (0.025 mL, 0.141 mmol) was dissolved in DMF (1 mL). The reaction was stirred for 48 h. The mixture was quenched with saturated NaHCO3 solution, and then EtOAc was added. The organic layer was separated, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by normal phase chromatography (4 g column) using a running gradient of 0-20% MeOH / DCM to give 22 mg of compound 23-4 as an oil. LCMS = 674.6 [M+H] + .

[0287] [ka] A solution of compound 23-4 (22 mg, 0.033 mmol) and TFA (200 μL, 2.60 mmol) in DCM (600 μL) was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo and purified by preparative HPLC to give 10.5 mg of compound 23. 1 H NMR (500 MHz, DMSO-d6) δ 8.33(d,J=6.2Hz,1H),8.22(dd,J=8.7,6.8Hz,1H),8.15(s,3H),7.86(s,3H) ,7.54(s,1H),7.10(dd,J=11.4,2.6Hz,1H),6.92(td,J=8.4,2.6Hz,1H),3.93 (s,3H),3.66(d,J=11.4Hz,2H),3.51-3.34(m,4H),3.15(d,J=5.9Hz,2H),2.1 9(d,J=13.4Hz,2H),1.83-1.67(m,2H),0.92-0.79(m,4H).LC-MS=474.2[M+H] + .

[0288] Example 24-0: N-(2-amino-2-methylpropyl)-8-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-1-thia-8-azaspiro[4.5]decane-4-carboxamide 1,1-dioxide [ka] Compound 24-0 was prepared in the following manner. [ka] To a stirred solution of dihydrothiophen-2(3H)-one (3.07 g, 30.11 mmol) in THF (50 mL) was added LiHMDS (30 mL, 30.11 mmol) at -78 °C and stirred for 1 h. tert-Butyl 4-oxopiperidine-1-carboxylate (5 g, 25.09 mmol) in THF (30 mL) was added to the reaction mixture at -78 °C and stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (3 × 50 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 30–40% EtOAc / n-hexane to give 6.12 g of compound 24-1 as a solid. 1 H NMR(600MHz,CDCl3)δ 3.94(br s,2H),3.68(br s,1H),3.28-3.25(m,2H),3.13(br s,2H),2.66(dd,J=13.2,7.0Hz,1H),2.43(dtd,J=12.0,7.0,2.9Hz,1H),2.06-2.03(m, 1H),1.67(dd,J=13.2,2.4Hz,1H)1.59-1.48(m,3H),1.45(s,9H).LC-MS=202.10[M-100] + (De-Boc), retention time = 1.47 minutes.

[0289] [ka] To a stirred solution of compound 24-1 (6.0 g, 19.9 mmol) in DCM (60 mL) at 0 °C was added EtN (27.7 mL, 199 mmol) and MsCl (3.08 mL, 39.81 mmol). The reaction was warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with saturated NaHCO solution and extracted with DCM (3 × 50 mL). The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 30–40% EtOAc / hexanes to give 1.2 g of compound 24-2 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 3.53(t,J=6.0Hz,2H),3.43(t,J=5.8Hz,2H),3.26(t,J=6.8Hz,2H),3.07-2.94(m,4H),2.34(t,J=6.0Hz,2H),1.46(s,9H).LC-MS=184.10[M-100] + (De-Boc), retention time = 1.54 minutes.

[0290] [ka] To a stirred solution of compound 24-2 (3.3 g, 2.82 mmol) in MeOH (330 mL) was added EtN (0.79 mL, 5.64 mmol). The reaction mixture was heated at 70 °C and stirred for 32 h. The reaction was concentrated in vacuo. The crude product was purified by normal phase chromatography using a running gradient of 5-10% EtOAc / n-hexane to give 1.2 g of compound 24-3 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 4.09(br s,2H),3.71(s,3H),3.06-2.68(m,5H),2.50-2.27(m,2H),2.14(td,J=13.0,4.6Hz,1H),1 .67(ddd,J=13.1,10.1,2.6Hz,2H),1.45(s,9H)1.42-1.48(m,1H).LC-MS=216.15[M-100] +( De-Boc), retention time = 1.61 min.

[0291] [ka] To a stirred solution of compound 24-3 (1.1 g, 2.85 mmol) in DCM (30 mL) was added mCPBA (1.4 g, 5.17 mmol) portionwise at 0 °C, and the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was filtered through a pad of CELITE, and the filtrate was washed with saturated NaHCO and the aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 1.1 g of compound 24-4 as a colorless liquid, which was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ 3.94(bs,2H),3.76(s,3H),3.50-3.32(m,2H),3.30-3.18(m,1H),3.15-3.06(m,1H),2.99(dd,J=11.1 ,6.3Hz,1H),2.51-2.40(m,1H),2.29-2.20(m,2H),2.16-2.02(m,2H),1.65-1.52(m,1H),1.45(s,9H).

[0292] [ka] To a stirred solution of compound 24-4 (1.1 g, 3.16 mmol) in THF:HO (10 mL, 1:1), LiOH·HO (0.19 g, 4.74 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with saturated citric acid to pH = 4 and extracted with DCM (50 mL × 2). The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo to give 0.9 g of compound 24-5 as a solid. 1H NMR(300MHz,DMSO-d6)δ 3.85-3.70(m,2H),3.46-3.35(m,2H),3.15(dt,J=13.3,9.0Hz,2H),2.94(dd,J=10.4,7.1Hz,1H), 2.31-2.11(m,2H),2.04(td,J=9.9,4.0Hz,3H),1.57(ddd,J=15.0,11.2,4.9Hz,1H),1.39(s,9H).

[0293] [ka] To a stirred solution of compound 24-5 (350 mg, 1.05 mmol) in DMF (5 mL) was added KCO (290 mg, 2.1 mmol) at 0 °C and stirred for 10 min. After that, MeI (296 mg, 2.1 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 7 h. Then, HO was added to the reaction mixture, the aqueous layer was extracted with EtOAc (2 × 30 mL), and the organic layer was washed with brine, dried over NaSO, and concentrated in vacuo to give 350 mg of compound 24-6 as an oil. 1 H NMR(400MHz,CDCl3)δ 3.95(bs,2H),3.75(s,3H),3.44(bs,1H),3.35(ddd,J=13.4,9.5,3.9Hz,1H),3.30-3.18(m,1H),3.15-3.06(m,1H),2.98(dd,J =11.2,6.5Hz,1H),2.45(ddt,J=14.1,11.2,9.3Hz,1H),2.30-2.17(m,2H),2.15-2.01(m,3H),1.65-1.52(m,1H),1.45(s,9H).

[0294] [ka] To a solution of compound 24-6 (350 mg, 1.0 mmol) in dioxane (3 mL) was added 4 M HCl in dioxane (3 mL) at 0 °C, then stirred at 0 °C to room temperature for 2 h. The reaction was concentrated in vacuo to give 350 mg of compound 24-7, which was used in the next step without purification. LC-MS = 248.0 [M+H] + , retention time = 0.15 min.

[0295] [ka] Compound 24-7 (1 equiv.), compound 1 (1 equiv.), DIPEA (2 equiv.), and MeCN (15-20 parts by volume) were heated to 100 °C for 90 min in a MW oven. The reaction mixture was cooled to room temperature and stirred at room temperature for 1 h until a precipitate formed. The solid was filtered and washed with MeCN and pentane. The crude material was purified by normal phase chromatography using a running gradient of 5 / 95 MeOH / DCM to give compound 24-8 as an oil. 1 H NMR(300MHz,CDCl3)δ 7.11(s,1H),3.82-3.77(m,2H),3.75(s,3H),3.67-3.34(m,3H),3.23-2.98(m,2H),2.59-2.18(m,4H),1.94-1.76(m,2H).

[0296] [ka] To a sealed tube containing compound 24-8 (1.0 equiv.) in dioxane:HO (4:1) was added KCO (3 equiv.), (4-fluoro-2-methoxyphenyl)boronic acid (1.5 equiv.), and PdCl(dppf)-DCM complex (5 mol%). After the reaction mixture was heated at 100 °C for 6 h, it was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo to give LC-MS = 495.05 [M+H]. + , retention time=1.48 minutes=481.15[M+H] +The crude material was obtained with a retention time of 1.40 min for the acid (Method 12). The crude compound was taken and THF:HO (5 mL, 4:1) was cooled to 0 °C, and LiOH (22 mg, 0.52 mmol) was added. The reaction mixture was stirred at room temperature for 5 h. The reaction was concentrated in vacuo, dissolved in HO, washed with DCM (10 mL × 3), and then the aqueous layer was acidified to acidic pH with KHSO. The aqueous layer was extracted with DCM (20 mL × 3), and the combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give compound 24-9 as a solid. LC-MS = 481.15 [M+H] + , retention time = 1.39 min.

[0297] [ka] To a solution of compound 24-9 (100 mg, 0.21 mmol) in DCM (8 mL) was added DIPEA (0.072 mL, 0.42 mmol), followed by tert-butyl (1-amino-2-methylpropan-2-yl)carbamate (31 mg, 0.17 mmol) at 0 °C and stirred for 5 min. T3P-50% (159 mg, 0.25 mmol) in EtOAc was added at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The aqueous layer was extracted with DCM (50 mL × 2). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 2–3% MeOH in DCM to give 50 mg of compound 24-10 as a solid. 1H NMR(300MHz,CDCl3)δ 8.11(dd,J=8.5,6.8Hz,1H),7.56(s,1H),6.82-6.67(m,2H),4.56(s,1H),3.91( s,3H),3.87-3.72(m,3H),3.69-3.52(m,1H),3.49-3.28(m,3H),3.24-3.09(m,1 H),2.80(dd,J=11.6,6.3Hz,1H),2.69-2.51(m,1H),2.41(d,J=13.9Hz,1H),2.3 0-2.15(m,3H),2.12-1.97(m,2H),1.59(s,9H),1.41(s,6H).LC-MS=651.35[M+H] + Retention time = 1.49 minutes.

[0298] [ka] To a solution of compound 24-10 in dioxane (10 mL) was added 4M HCl in dioxane (10 mL) at 0 ° C., followed by stirring at 0 ° C. to room temperature for 2 hours. The solvent was evaporated in vacuo. The crude compound was purified by trituration with MeCN and pentane, filtered, and the resulting solid was dried to give compound 24 as the HCl salt. 1 H NMR (300 MHz, MeOD-d4) δ 8.55(t,J=5.7Hz,1H),8.28(dd,J=8.8,6.5Hz,1H),7.89(s,1H),7.02(dd,J=11 .0,2.5Hz,1H),6.88(ddd,J=8.8,8.1,2.5Hz,1H),3.97(s,3H),3.94-3.83(m,2H ),3.77-3.64(m,1H),3.60-3.47(m,2H),3.27-3.21(m,1H),3.20-3.05(m,2H), 2.57-2.40(m,2H),2.40-2.05(m,4H),1.28(d,J=4.0Hz,6H).LC-MS=551.6[M+H] + , retention time = 1.32 min.

[0299] Compound 25-0: 2-(4-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)propan-2-ol [ka] Compound 25-0 was prepared in the following manner. [ka] A mixture of 1-benzylpiperidin-4-one (30 g, 159 mmol), (NH)CO (107 g, 1113 mmol), and NaCN (23.4 g, 477 mmol) in HO (210 mL) and EtOH (210 mL) was stirred at 60° C. for 12 h. The reaction mixture was filtered, and the resulting solid was washed with HO (150 mL) and dried to give 37 g of compound 25-1 as a solid. 1 H NMR(DMSO-d6,400MHz)δ 1.51(br,d,J=13.0Hz,2H),1.73-1.90(m,2H),2.15-2.35(m,2H),2.60-2.77(m,2H),3.48(s,2H),7.18-7.39(m,5H).

[0300] [ka] A mixture of compound 25-1 (37 g, 143 mmol) and KOH (80 g, 1430 mmol) in HO (400 mL) was stirred at 100 °C for 24 h. The mixture was cooled to 15 °C. The pH of the reaction was adjusted to 6 with aqueous HCl (6 M) at 0 °C. The reaction mixture was filtered, washed with HO and MTBE, and concentrated in vacuo to give 31 g of compound 25-2 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 1.86(br,s,2H),2.11(br,d,J=6.1Hz,2H),2.80-3.06(m,4H),3.92(br,s,2H),7.29-7.49(m,5H).

[0301] [ka] To a solution of compound 25-2 (15 g, 64 mmol) and NaOH (10.2 g, 256 mmol) in HO (50 mL) and dioxane (50 mL) was added (Boc)O (41.9 g, 192 mmol). The resulting mixture was stirred at 15 °C for 3 h. The mixture was filtered, and the resulting solid was washed with HO (50 mL) and dried to give 17 g of compound 25-3 as a white solid. 1 H NMR(400MHz,MeOD-d4)δ 1.43(s,9H),2.35-2.11(m,4H),2.99-2.77(m,2H),3.16(br,s,2H),4.07(br,s,2H),7.54-7.20(m,5H).LC-MS=335.3[M+H] + .

[0302] [ka] To a solution of compound 25-3 (8 g, 20 mmol) in DCM (50 mL) and MeOH (5 mL) was added TMSCHN2 (2 M, 4.6 g, 40 mmol). The resulting mixture was stirred at 15 °C for 3 h. The mixture was concentrated in vacuo. The reaction was purified by normal-phase chromatography using a running gradient of petroleum ether / EtOAc from 1:0 to 1:2 to give 4.5 g of compound 25-4 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 1.36(br,s,9H),1.81-1.88(m,2H),2.12-2.29(m,2H),3.32(br,s,4H),3.43(s,2H),3.58(s,3H),7.20-7.37(m,5H).LC-MS=349.3[M+H] + .

[0303] [ka] To a solution of compound 25-5 (4.5 g, 12 mmol) in anhydrous THF (50 mL) was slowly added MeMgBr (3 M in EtO, 12.6 mL, 37.8 mol) at -15 °C. The mixture was stirred for 0.5 h and then warmed to 15 °C for 15.5 h. The mixture was poured into saturated NH Cl (30 mL) solution and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over MgSO and concentrated in vacuo. The crude product was purified by preparative HPLC to give 1.6 g of compound 25-5 as a solid. 1 H NMR(400MHz,DMSO-d6)δ 1.03(s,6H),1.37(s,9H),1.51-1.69(m,2H),1.89-2.11(m,4H),2.58(br,d,J=11.0H z,2H),3.39(s,2H),4.49(s,1H),6.20(s,1H),7.17-7.35(m,5H).LC-MS=349.4[M+H] + .

[0304] [ka] A suspension of compound 25-5 (1.6 g, 4.6 mmol) and Pd / C (2 g, 10% content) in MeOH (1 mL) was stirred under H (15 psi) at room temperature for 1 h. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give 968.5 mg of compound 25-6 as a solid. 1 H NMR(400MHz,MeOD-d4)δ 1.17(s,6H),1.45(s,9H),1.62(dt,J=4.3,13.2Hz,2H),2.00-2.15(m,2H),2.64-2.79(m,2H),2.80-2.92(m,2H).LC-MS=259.2[M+H] + .

[0305] The following compound 25-0 was prepared by the same route used to prepare compound 4-0.

[0306] [Table 40]

[0307] Example 26-0: 4-(aminomethyl)-1-(5-(4-(1-hydroxycyclobutyl)-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-ol [ka] Compound 26-0 was prepared in the following manner. [ka] To a solution of compound 26-1 (500 mg, 2.06 mmol) in DCM (25 mL) at 0 °C, imidazole (420 mg, 6.17 mmol), TBDMS-Cl (620 mg, 4.11 mmol), and DMAP (5 mg) were added. The resulting solution was stirred at room temperature for 18 h. The reaction was diluted with HO and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 0–2% EtOAc / n-hexane to give 410 mg of compound 26-2 as an oil. 1 H NMR(300MHz,CDCl3)δ 7.41(d,J=8.1Hz,1H),7.06(d,J=2.0Hz,1H),6.59(dd,J=8.3,2.1Hz,1H),3.90(s,3H) ),1.70-1.60(m,1H),1.26-1.14(m,3H),1.02-0.95(m,3H),0.89(s,9H),0.02(s,6H).

[0308] [ka] Compound 26-2 (0.15 mmol), B(O iA solution of 26-3 (1.0 equiv.), Pd(dppf)Cl-DCM complex (5 mol%), and 1M aqueous NaCO (2.0 equiv.) was purged under argon for several minutes, after which the reaction tube was microwaved at 120 °C for 30 min. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo to give 365 mg of compound 26-3 as a brown liquid.

[0309] [ka] A solution of compound 3 (1.0 equiv.) in dioxane / HO (4:1), KCO (3.0 equiv.), compound 26-3 (1.5 equiv.), and Pd(dppf)Cl-DCM complex (5 mol%) was added. The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was purified by preparative HPLC to give 70 mg of compound 26-4 as a solid. 1 H NMR (300 MHz, CDCl3) δ 8.18(d,J=8.2Hz,2H),7.67(s,1H),7.17(d,J=1.7Hz,1H),6.77(dd,J=8.2,1 .8Hz,1H),5.04-4.85(m,1H),3.94(s,3H),3.78-3.64(m,2H),3.62-3.45(m,2 H),3.18(d,J=6.2Hz,2H),1.75-1.70(m,3H),1.70-1.55(m,4H),1.46(s,9H), 1.35-1.15(m,3H),1.08-0.99(m,1H),0.91(s,6H),0.13--0.20(m,9H);LC-MS m / z 631.0[M+H] + , retention time = 1.76 min.

[0310] [ka] Compound 26 was prepared from compound 26-4 (40 mg) using Boc deprotection procedure B. The crude material was purified by trituration with 5% MeOH in MeCN followed by trituration with pentane to give 26 mg of compound 26 as a solid. 1 H NMR(300MHz,MeOD-d4)δ 8.53(dd,J=8.1,3.4Hz,1H),8.09(s,1H),7.84-7.64(m,2H),4.06(s,3H),3.94-3.76(m,2H),3.76-3.55(m,2H) ,3.26-3.16(m,3H),3.19-3.02(m,2H),2.99(s,2H),1.92-1.74(m,3H),1.26-1.13(m,2H);LC-MS=415.85[M+H] + , retention time = 1.30 min.

[0311] Example 27-0: ((1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-4-((methylsulfonyl)methyl)piperidin-4-yl)methanamine [ka] Compound 27-0 was prepared in the following manner. [ka] To a solution of 1-(tert-butyl) 4-ethyl 4-(iodomethyl)piperidine-1,4-dicarboxylate in DMF (2 mL) was added NaSMe (48.5 mg). The reaction mixture was stirred at room temperature for 14 h. After dilution with EtOAc, the mixture was washed twice with HO and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by normal-phase chromatography using a running gradient of 0-10% EtOAc / heptane to give 180 mg of compound 27-1 as an oil.

[0312] [ka] To a solution of compound 27-1 in DCM (1.8 mL) was added mCPBA at -5 °C. The reaction mixture was stirred at -5 °C for 15 minutes, then at room temperature for 30 minutes. The reaction was quenched with saturated aqueous NaHCO3. The mixture was extracted with EtOAc, and the organic layer was washed with saturated aqueous NaHCO3, H2O, and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was dissolved in THF (1.2 mL), and LiAlH4 (2 M in THF) was added at 0 °C. The reaction mixture was stirred at 0 °C to room temperature for 4 hours. The reaction was quenched with 2 M NaOH and water, then diluted with EtOAc, and Na2SO4 was added. The mixture was filtered and concentrated in vacuo. The residue was dissolved in EtOAc-DCM, then filtered and concentrated in vacuo to give 177 mg of compound 27-2 as an oil.

[0313] [ka] To a solution of compound 27-2 in MeOH (0.5 mL) was added 4M HCl in dioxane (0.8 mL). The reaction mixture was stirred at room temperature for 30 minutes. Then, the mixture was concentrated in vacuo. The residue was dissolved in EtOH (1.5 mL). To this solution were added DIPEA (0.380 mL, 2.30 mmol) and compound 1 (140 mg, 0.424 mmol). The reaction mixture was stirred at 100° C. for 3 hours. The resulting precipitate was triturated with MeCN, filtered, washed with MeCN, and dried to give 108 mg of compound 27-3 as a solid. LC-MS=457.1 [M+H] + .

[0314] [ka] A mixture of compound 27-3 (66.9 mg, 0.147 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (32.4 mg, 0.191 mmol), and PdCl(PhP) (5.15 mg, 7.33 μmol) in 2M NaCO and dioxane (0.5 mL) was stirred at 100 °C for 1 h. This mixture was purified by normal-phase chromatography using a running gradient of 0 to 100% EtOAc / hHeptane followed by 95 / 5 MeOH / DCM to give 67.5 mg of compound 27-4. LC-MS = 455.3 [M+H] + .

[0315] [ka] To a solution of compound 27-4 (67 mg, 0.147 mmol) in DCM (1.8 mL) was added EtN (0.103 mL, 0.737 mmol), DMAP (1 mg, 8.19 μmol), and MsCl (0.029 mL, 0.369 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. Additional MsCl (0.02 mL) was added. The reaction mixture was stirred at room temperature for 30 min. After dilution with EtOAc, the mixture was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was dissolved in DMF (0.5 mL) and NaN (90 mg, 1.38 mmol), and 15-crown-5 (0.233 mL, 1.18 mmol) was added. The reaction mixture was stirred at 60 °C for 17 h. After dilution with EtOAc, the mixture was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 60 mg of compound 27-5. LC-MS=480.2 [M+H] + .

[0316] [ka] To a solution of compound 27-5 (60 mg, 0.125 mmol) in THF (0.8 mL) and HO (0.2 mL) was added PhP (65.6 mg, 0.250 mmol). The reaction mixture was stirred at 60 °C for 6.5 h. After dilution with EtOAc, the mixture was extracted with aqueous HCl and water. The combined aqueous layers were washed with EtOAc, then basified with aqueous NaOH and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 31.4 mg of compound 27. 1 H NMR(400MHz,DMSO-d6)δ 8.22(dd,J=8.7,6.8Hz,1H),7.94(s,3H),7.59(s,1H),7.09(dd,J=11.4,2 .6Hz,1H),6.93(td,J=8.4,2.5Hz,1H),3.92(s,3H),3.69(d,J=16.0Hz,4H ),3.54(ddd,J=13.4,9.6,3.4Hz,2H),3.26(d,J=6.0Hz,2H),3.07(s,3H), 2.18-1.83(m,2H),1.77(ddd,J=13.9,10.1,4.3Hz,2H).LC-MS=454.1[M+H] + .

[0317] Example 28-0: 1-(4-(aminomethyl)-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-4-yl)-N,N-dimethylmethanesulfonamide [ka] Compound 28-0 was prepared in the following manner. [ka] To a solution of 1-(tert-butyl) 4-ethyl 4-(iodomethyl)piperidine-1,4-dicarboxylate (250 mg, 0.629 mmol) in DMF (2 mL) was added potassium ethanethioate (144 mg, 1.259 mmol). The reaction mixture was stirred at room temperature for 15 h. Additional potassium ethanethioate (60 mg) was added, and the reaction mixture was then stirred at room temperature for 13 h. After dilution with EtOAc, the mixture was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was purified by normal-phase chromatography using a running gradient of 0–10% EtOAc / heptane to give 165 mg of compound 28-1 as an oil.

[0318] [ka] To NCS (255 mg, 1.911 mmol) was added a solution of 3 M HCl (0.167 mL), HO (0.06 mL), and MeCN (1 mL). To this mixture was added a solution of compound 28-1 in MeCN (1 mL) at 0 °C. The reaction mixture was stirred at room temperature for 50 minutes. After dilution with EtOAc, the mixture was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo. The resulting residue was dissolved in MeCN (1.5 mL), and aqueous MeNH (0.3 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. After dilution with EtOAc, the mixture was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo to give compound 28-2.

[0319] [ka] To a solution of compound 28-2 (130 mg, 0.343 mmol) in THF (1.2 mL) was added LiAlH (2 M, 0.24 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction was quenched by adding 2 M NaOH and water. The mixture was diluted with EtOAc, dried over NaSO, filtered, and concentrated in vacuo to give 88 mg of compound 28-3.

[0320] [ka] To a solution of compound 28-3 (88 mg, 0.262 mmol) in MeOH (0.5 mL) was added HCl in dioxane (0.8 mL). The reaction mixture was stirred at room temperature for 1.5 h. The mixture was then concentrated in vacuo. The residue was dissolved in EtOH (1.5 mL), and then compound 1 (78 mg, 0.235 mmol) and DIPEA (0.8 mL, 3.20 mmol) were added. The reaction mixture was stirred at 100° C. for 3 h. The mixture was concentrated in vacuo. The residue was purified by normal phase chromatography using a running gradient of 0-100% EtOAc / heptane to give 76 mg of compound 28-4. LC-MS=486.1 [M+H] + .

[0321] [ka] A mixture of compound 28-4 (76 mg, 0.157 mmol), (4-fluoro-2-methoxyphenyl)boronic acid (334.6 mg, 0.204 mmol), and PdCl(PhP) (5.5 mg, 7.83 μmol) in aqueous NaCO (2 M, 0.391 mL, 0.783 mmol) and dioxane (0.5 mL) was stirred at 100 °C for 1 h. The mixture was purified by normal phase chromatography using a running gradient of 0 to 100% EtOAc / heptane, then 100% (10:90 MeOH:DCM) to give 55.9 mg of compound 28-5. LC-MS = 484.2 [M+H] + .

[0322] [ka] To a solution of compound 28-5 (55 mg, 0.114 mmol) in DCM (0.8 mL) was added EtN (0.079 mL, 0.569 mmol), DMAP (13.90 mg, 0.114 mmol), and MsCl (0.022 mL, 0.284 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 30 min. After dilution with EtOAc, the mixture was washed with HO and brine, dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in DMF (0.5 mL), and then NaN (59.2 mg, 0.910 mmol) and 15-crown-5 (0.180 mL, 0.910 mmol) were added. The reaction mixture was stirred at 60 °C for 1 h and then at 100 °C for 7 h. An additional 26 mg of NaN was added. The reaction mixture was stirred at 100 °C for 13 h. After dilution with EtOAc, the mixture was washed with H2O and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 44 mg of compound 28-6. LC-MS=509.2 [M+H] + .

[0323] [ka] To a solution of compound 28-6 (44 mg, 0.087 mmol) in THF (0.7 mL) and HO (0.16 mL) was added PhP (45.4 mg, 0.173 mmol). The reaction mixture was stirred at 60 °C for 9 h. After dilution with EtOAc, the mixture was extracted with aqueous HCl and water. The combined aqueous layers were washed with EtOAc, basified with aqueous NaOH, and extracted with EtOAc. The organic layer was dried over NaSO, filtered, and concentrated in vacuo. The residue was dissolved in MeOH, treated with HCl in dioxane, and then concentrated in vacuo. The residue was purified by preparative HPLC to give 23.6 mg of compound 28. 1H NMR(400MHz,DMSO-d6)δ 8.23(dd,J=8.7,6.9Hz,1H),7.88(s,3H),7.53(s,1H),7.08(dd,J=11.4,2.5Hz,1H),6.92(td,J=8.5,2.6Hz,1H),3.92(s,3H) ),3.58(m,4H),3.38(s,2H),3.22(d,J=5.9Hz,2H),1.94-1.84(m,2H),1.77(ddd,J=13.6,8.4,4.6Hz,2H).LC-MS=483.2[M+H] + .

[0324] Compound 29-0: ((3R,5S)-5-amino-1-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)piperidin-3-ol [ka] Compound 29-0 was prepared by the same route used to prepare compound 4-0 using the appropriate starting materials. [ka] To a mixture of compound 29-1 (18.3 mg, 0.039 mmol), 4-nitrobenzoic acid (7.92 mg, 0.047 mmol), and Ph3P (12.43 mg, 0.047 mmol) in THF (0.8 mL) was added diisopropyl azodicarboxylate (9.33 μL, 0.047 mmol). The reaction mixture was stirred at room temperature for 14 h and then concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 0–100% EtOAc / heptane to give the intermediate compound, which was treated with MeOH / 4 M HCl in dioxane at room temperature for 1 h. The reaction mixture was concentrated in vacuo. The residue was then triturated with MeOH / MeCN and filtered. The resulting solid was washed with CH3CN, dried, and then treated with 2 M aqueous NaOH in MeOH at room temperature for 1 h. After dilution with water, the mixture was extracted with EtOAc. The combined organic layers were washed with aqueous NaOH, dried over NaSO, filtered, and concentrated in vacuo. The residue was then treated with 4M HCl in dioxane, concentrated in vacuo, and then diluted with water and lyophilized to give 2.7 mg of compound 29 as a solid. 1 1 H NMR suggested that the stereochemistry of the -OH was inverted. 1 H NMR(500MHz,MeOD-d4)δ 8.27(dd,J=8.7,6.5Hz,1H),7.90(s,1H),7.03(dd,J=11.0,2.4Hz,1H),6.88(td,J=8.4,2.4Hz,1H),4.20-4.09(m,2H),3.96 (s,3H),3.83(dd,J=14.1,3.0Hz,1H),3.73-3.66(m,3H),2.21(dt,J=14.4,3.6Hz,1H),2.09-2.01(m,1H).LCMS=364.2[M+H] + .

[0325] Example 30-0: (4S,4aR,7aS)-6-(5-(2-ethoxy-6-isopropylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine [ka] Compound 30-0 was prepared in the following manner. [ka] NaH (60% wet with paraffin) (21.0 g, 526.3 mmol) was suspended in THF (300 mL) under N and cooled to 0 °C. 1,3-Dihydroxypropane (40 g, 526.3 mmol) dissolved in THF (200 mL) was added dropwise via a dropping funnel and stirred at 0 °C for 1 h. TBDPS-Cl (144.6 g, 526.3 mmol) dissolved in THF (100 mL) was added via an addition funnel at 0 °C to the reaction mixture and stirred for 2 h. The reaction mixture was quenched with ice-cold HO and extracted with EtO. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 30 / 70 EtOAc / n-hexane to give 90 g of compound 30-1 as a solid. 1 H NMR(300MHz,CDCl3)δ 7.75-7.57(m,4H),7.51-7.31(m,6H),3.91-3.79(m,4H),2.38(t,J=5.6Hz,1H),1.81(p,J=5.6Hz,2H),1.05(s,9H).

[0326] [ka] Oxalyl chloride (19.0 mL, 214.96 mmol) was dissolved in DCM (200 mL) under N and cooled to −78 °C. DMSO (34.0 mL, 429.93 mmol) dissolved in DCM (200 mL) was added dropwise via an addition funnel at −78 °C and stirred at the same temperature for 1 h. Compound 30-1 (45.0 g, 143.31 mmol) dissolved in DCM (200 mL) was added to the reaction mixture at −78 °C and stirred for an additional 2 h. The reaction mixture was quenched with EtN (125 mL) at −78 °C and warmed to room temperature for 15 min, after which HO (200 mL) was added. The aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 45 g of compound 30-2. 1 H NMR(300MHz,CDCl3)δ 9.82(t,J=2.2Hz,1H),7.71-7.62(m,4H),7.48-7.31(m,6H),4.02(t,J=6.0Hz,2H),2.68-2.48(m,2H),1.04(s,9H).

[0327] [ka] Compound 30-2 (82.1 g, 263 mmol) was dissolved in MeOH (1.60 L) under N and cooled to 0 °C. Pyridine (80.5 g, 1.012 mol) was added dropwise, followed by the addition of hydroxylamine hydrochloride (27.4 g, 395 mmol) portionwise at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo to give a crude residue, which was dissolved in HO and extracted with EtOAc. The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 86 g of compound 30-3. 1 H NMR(400MHz,CDCl3)δ 7.79-7.69(m,4H),7.56-7.30(m,7H),4.19-4.14(m,1H),3.87-3.84(m,2H),2.69-2.65(m,1H),2.51-2.46(m,1H),1.16(s,9H).

[0328] [ka] Compound 30-3 (86.0 g, 263 mmol) was dissolved in DMF (860 mL) under N and cooled to 0 °C. NCS (38.6 g, 289 mmol) was added portionwise to the reaction mixture at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with ice-cold HO and extracted with EtOAc. The combined organic layers were washed with cold HO (150 mL × 3), brine, dried over NaSO, and concentrated in vacuo to give 95 g of compound 30-4. 1 H NMR(400MHz,CDCl3)δ 7.79-7.69(m,4H),7.56-7.30(m,7H),4.19-4.14(m,1H),3.87-3.84(m,2H),2.69-2.65(m,1H),2.51-2.46(m,1H),1.16(s,9H).

[0329] [ka] Compound 30-4 (47.0 g, 130 mmol) and benzyl 2,5-dihydro-1H-pyrrole-1-carboxylate (24.0 g, 118 mmol) were dissolved in IPA (500 mL) at room temperature. NaHCO (56.0 g, 667 mmol) was added to the reaction mixture, which was heated to 50 °C and stirred for 16 h. The reaction mixture was quenched with ice-cold HO and extracted with EtOAc. The combined organic layers were washed with cold water, brine, dried over NaSO, and concentrated in vacuo. The crude residue was purified by normal-phase chromatography (80 g column) using a running gradient of 35–45% EtOAc / n-hexane to give 11.5 g of compound 30-5. 1 H NMR(400MHz,CDCl3)δ 7.68-7.67(m,4H),7.47-7.30(m,11H),5.16-5.12(m,2H),3.96-3.86(m,5H),3.60-3 .50(m,2H),2.76-2.73(m,2H),2.10-2.08(m,1H),1.10(s,9H).LC-MS=546.6[M+H2O] + .

[0330] [ka] Compound 30-5 (11.5 g, 21.8 mmol) was dissolved in MeOH:THF (3:1) (560 mL) under N and cooled to -30 °C. NiCl 6H O (15.5 g, 65.3 mmol) was added. NaBH (8.27 g, 218 mmol) was added portionwise to the reaction mixture at -30 °C and stirred for 2 h. Et N (7 mL) was added to the reaction mixture and stirred at -30 °C for 15 min. The reaction mixture was filtered through a CELITE pad and washed with excess MeOH. The filtrate was concentrated in vacuo to give a crude residue, which was dissolved in EtOAc, washed with brine, dried over Na SO , and concentrated in vacuo to give 10.4 g of compound 30-6 as a solid. LC-MS = 533.20 [M+H] + .

[0331] [ka] Compound 30-6 (10.4 g, 19.6 mmol) was dissolved in DCM (160 mL) and cooled to 0 °C. EtN (5.94 g, 58.8 mmol) and (Boc)O (6.41 g, 29.4 mmol) were added, and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with HO and extracted with DCM. The combined organic layers were washed with water, brine, dried over NaSO, and concentrated in vacuo. The crude residue was purified by normal-phase chromatography (80 g column) using a running gradient of 30–65% EtOAc / n-hexane to give two diastereomeric products, compounds 30-7 and 30-8.

[0332] Major peak compound 30-7: rac-benzyl (3S,4R)-3-hydroxy-4-((S)-2,2,11,11-tetramethyl-9-oxo-3,3-diphenyl-4,10-dioxa-8-aza-3-siladodecan-7-yl)pyrrolidine-1-carboxylate (5.10 g): 1H NMR(400MHz,MeOD-d4)δ 7.69-7.66(m,4H),7.47-7.30(m,11H),5.17(s,2H),4.20(s,1H),4.00-3.70(m,3H),3.60-3.45(m,2H),3.31-3.29 (m,2H),2.21-2.19(m,1H),2.11-2.09(m,1H),1.77-1.75(m,1H),1.47(s,9H),1.08(s,9H).LCMS=533.58[M-Boc+H] + .

[0333] Minor peak compound 30-8: rac-benzyl (3S,4R)-3-hydroxy-4-((R)-2,2,11,11-tetramethyl-9-oxo-3,3-diphenyl-4,10-dioxa-8-aza-3-siladodecan-7-yl)pyrrolidine-1-carboxylate (3.60 g): 1 H NMR(400MHz,CDCl3)δ 7.68-7.67(m,4H),7.47-7.30(m,11H),6.20-6.10(m,1H),5.16-5.12(m,2H),4.20(s,1H),4.05-3.75(m,3H),3.70-3. 60(m,1H),3.36-3.34(m,1H),3.21-3.19(m,1H),2.10-2.08(m,2H),1.45(s,9H),1.10(s,9H).LCMS=533.63[M-Boc+H] + .

[0334] [ka] Compound 30-7 (5.10 g, 8.07 mmol) was dissolved in THF (80 mL) and cooled to 0 °C. TBAF (1 M in THF, 2.53 g, 9.68 mmol) was added at 0 °C, and the mixture was stirred at room temperature for 30 minutes. The mixture was quenched with HO and extracted with EtOAc. The combined organic layers were washed with HO and brine, then dried over NaSO and concentrated in vacuo to give a crude residue, which was purified by trituration with n-pentane to give 3 g of compound 30-9. 1H NMR(400MHz,MeOD-d4)δ 7.39-7.35(m,5H),5.12(s,2H),4.30-4.21(m,1H),3.95-3.82(m,1H),3.78-3.50(m,6H),2.35-2.15(m,1H),2.15-1.95(m,1H),1.50(br s,9H).LC-MS=295.2[M-Boc+H] + .

[0335] [ka] To a solution of compound 30-9 (3.00 g, 7.61 mmol) in DCM (60 mL) and EtN (0.770 g, 7.61 mmol) was added a solution of MsCl (0.870 g, 7.61 mmol) in DCM (5 mL) at 0 °C, and the resulting mixture was stirred at 0 °C for 2 h. The mixture was concentrated in vacuo to give 3.60 g of compound 30-10, which was used in the next step without further purification. 1 H NMR(400MHz,CDCl3)δ 7.75-7.46(m,5H),5.30-5.10(m,2H),4.73-4.71(m,1H),4.35-4.34(m,1H),4.05-3.99(m,1H),3.84-3.45 (m,3H),3.44-3.14(m,1H),3.14(s,3H),2.95-2.71(m,1H),2.35-2.15(m,1H),2.15-1.95(m,1H),1.35(br s,9H).LC-MS=373.1[M-Boc+H] + .

[0336] [ka] Compound 30-10 (3.60 g, 7.63 mmol) was dissolved in THF (80.0 mL), and CsCO (7.46 g, 22.9 mmol) was added at 0 °C. The mixture was heated to reflux for 16 h. The mixture was filtered through a CELITE pad, and the pad was washed with THF. The filtrate was concentrated in vacuo and purified by normal-phase chromatography (basic alumina column) using a running gradient of 30–45% EtOAc / n-hexane to give 1.40 g of compound 30-11. 1 H NMR(400MHz,CDCl3)δ 7.41-7.30(m,5H),5.21-5.12(m,2H),4.83-4.81(m,1H),4.15-4.13(m,1H),3.86-3.73(m,2H),3.70- 3.48(m,3H),3.47-3.39(m,2H),2.27-2.25(m,1H),2.06-2.08(m,1H),1.52(s,9H).LC-MS=377.3[M+H] + .

[0337] [ka] Compound 30-11 (0.400 g, 1.06 mmol) was dissolved in t-BuOH (60 mL), then Pd / C (10% anhydrous weight, 0.2 g) and Pd(OH) (20% dry weight, 0.2 g) were added and the mixture was heated to 10 kg / cm 2 The mixture was stirred at room temperature for 45 minutes under H pressure. The mixture was filtered through a pad of CELITE and the pad was washed with DCM. The filtrate was concentrated in vacuo to give 0.253 g of compound 30-12. 1 H NMR(400MHz,CDCl3)δ 4.85-4.83(m,1H),4.10-4.08(m,1H),3.91-3.82(m,2H),3.25-3.03(m,4H),2.70- 2.40(m,3H),2.20-2.00(m,2H),1.62-1.59(m,1H),1.44(s,9H).LC-MS=243.2[M+H] + .

[0338] [ka] A solution of compound 1 (300 mg, 0.909 mmol), compound 30-12 (264 mg, 1.091 mmol), and EtN (0.26 mL, 1.865 mmol) in dioxane (10 mL) was heated to 80° C. for 8 hours, then at 100° C. for 4 hours. The reaction was cooled to room temperature and concentrated. The crude material was redissolved in DCM and washed with 0.1 M HCl (20 mL). The aqueous layer was extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO, dried over NaSO, and concentrated in vacuo to give 421 mg of compound 30-13 as a solid. LC-MS=492.2 [M+H] + .

[0339] [ka] A mixture of compound 30-13 (190 mg, 0.387 mmol), compound 39 (162 mg, 0.773 mmol), PdCl(dppf)-DCM complex (31.6 mg, 0.039 mmol), and KPO (246 mg, 1.160 mmol) was placed under N for several minutes, then dioxane (2.5 mL) and HO (0.5 mL) were added. The vial was placed under N for an additional minute, and the reaction was heated at 90 °C for 1 h. The reaction was concentrated in vacuo and purified by normal-phase chromatography (40 g column) using a running gradient of 0–40% (3:1 EtOAc:EtOH) / heptane to give the racemic mixture. Chiral purification was performed using SFC (Method 3) to give 38 mg of the first eluting peak compound 30-14 (97.78% retention = 4.12 min) and 59 mg of the second eluting peak compound 30-15 (87.3% retention = 5.02 min). The second peak was purified again using the same SFC method, recovering 6 mg of the first eluting compound and 31 mg of the second eluting peak, which showed 96.8% retention = 5.38 min.

[0340] [ka] Compound 30-14 (44 mg, 0.084 mmol) underwent Boc deprotection after treatment with formic acid (0.5 mL, 13.04 mmol). The reaction was stirred at room temperature for 24 hours. The reaction was concentrated in vacuo and purified by preparative HPLC to assign 21.3 mg of one enantiomer of compound 30 as a single compound with unknown absolute stereochemistry. 1 H NMR(400MHz,DMSO-d6)δ 8.59(d,J=7.7Hz,1H),7.59(s,1H),6.97(d,J=7.8Hz,1H),4.47(q,J=7.0Hz,2H),4.40( t,J=3.7Hz,1H),3.81(t,J=11.3Hz,1H),3.66(dd,J=11.1,4.1Hz,1H),3.60(d,J=9.2Hz, 2H),3.47(dt,J=9.9,4.3Hz,2H),3.25(s,1H),2.95(p,J=6.8Hz,1H),2.26(d,J=9.7Hz, 1H),1.94(s,1H),1.42(t,J=7.0Hz,3H),1.33(d,J=13.9Hz,1H),1.26(d,J=6.9Hz,6H).C 21 H 28 MS m / z calculated for N6O2S: 428.6, observed: 429.5 [M+H] + Chiral analysis (Method 4): 100% retention = 5.46 min.

[0341] The same N-Boc deprotection procedure was carried out on the second eluting peak, compound 30-15, and the resulting compound was assigned as a single compound, compound 30-16, of unknown absolute stereochemistry. 1H NMR(400MHz,DMSO-d6)δ 8.59(d,J=7.7Hz,1H),7.59(s,1H),6.97(d,J=7.8Hz,1H),4.47(q,J=7.0Hz,2H),4.40( t,J=3.7Hz,1H),3.81(t,J=11.3Hz,1H),3.66(dd,J=11.1,4.1Hz,1H),3.60(d,J=9.2Hz, 2H),3.47(dt,J=9.9,4.3Hz,2H),3.25(s,1H),2.95(p,J=6.8Hz,1H),2.26(d,J=9.7Hz, 1H),1.94(s,1H),1.42(t,J=7.0Hz,3H),1.33(d,J=13.9Hz,1H),1.26(d,J=6.9Hz,6H).C 21 H 28 MS m / z calculated for N6O2S: 428.6, observed: 429.5 [M+H] + Chiral analysis (Method 4): 100% retention = 4.60 min.

[0342] The following compounds were prepared by the same route used to prepare compound 30-0 using the appropriate starting materials.

[0343] [Table 41]

[0344] [Table 42]

[0345] [Table 43]

[0346] Example 31-0: ((4S,4aS,7aR)-6-(5-(4-fluoro-2-methoxyphenyl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine [ka] Compound 31-0 was prepared in the following manner. [ka] Compound 30-8 (0.86 g, 1.358 mmol) was dissolved in THF (10 mL) and cooled to 0 °C. TBAF (1 M in THF) (1.6 mL, 1.630 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with H O and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over Na SO and concentrated in vacuo at 35 °C. The crude residue was purified by trituration with n-pentane to give 800 mg of compound 31-1 as a solid. LC-MS = 295.15 [M-100] + , retention time = 1.44 min.

[0347] [ka] To a solution of compound 31-1 (800 mg, 2.21 mmol) in THF (60 mL) was added EtN (402 mg, 3.98 mmol) at 0 °C. Then, MsCl (378 mg, 3.32 mmol) was added dropwise at 0 °C, and the resulting reaction mixture was stirred for 2 h. The reaction mixture was diluted with HO and extracted with DCM. The organic layer was dried over NaSO and concentrated in vacuo to give 750 mg of compound 31-2. LC-MS = 373.0 [M-100] + , retention time = 1.52 min.

[0348] [ka] To a solution of compound 31-2 (750 mg, 1.58 mmol) in THF (15 mL) was added CsCO (1.54 g, 4.76 mmol) at 0 °C, and the reaction mixture was then heated to 75 °C and stirred for 16 h. The reaction was diluted with EtOAc, and the combined organic layers were washed with water, dried over NaSO, and concentrated in vacuo. The crude residue was purified by normal phase chromatography using a running gradient of 5 / 95 MeOH / DCM. The product was taken up in ethyl acetate, MTBE was added, stirred for 10 h, and the resulting suspension was filtered and dried to give 400 mg of compound 31-3 as a solid. LC-MS = 277.2 [M-100] + (De-Boc), retention time = 1.52 minutes.

[0349] [ka] To a solution of compound 31-3 (350 mg, 0.13 mmol) in t-BuOH (50 mL), Pd / C (10% dry basis) (0.2 g) and Pd(OH) (20% dry basis) (50 mg) were added, and the reaction mixture was stirred under H at room temperature for 7 h. The reaction mixture was filtered through a CELITE pad and washed with excess DCM. The filtrate was concentrated in vacuo to give 300 mg of compound 31-4. LC-MS=243.0 [M+H] + , retention time = 0.83 min.

[0350] [ka] A suspension of compound 31-4 (1 equiv.), compound 1 (1 equiv.), and DIPEA (2 equiv.) in MeCN (20 parts by volume) was heated in a microwave oven for 90 minutes at 100° C. The reaction mixture was cooled to room temperature. The solid was filtered and washed with excess cold MeCN to give 250 mg of compound 31-5 as a solid. 1H NMR(300MHz,DMSO-d6)δ 7.08(s,1H),7.06-6.99(m,1H),4.13(t,J=3.3Hz,1H),3.97-3.80(m,2H),3.73-3.61(m,1H),3.58-3.43(m,1H) ),3.43-3.35(m,2H),2.84-2.70(m,1H),1.76-1.59(m,1H),1.56-1.46(m,2H),1.40(s,9H).LC-MS=492.0[M+H] + , retention time = 1.51 min.

[0351] [ka] To a solution of compound 31-5 (1.0 equiv.) in dioxane / HO (4:1), KCO (3.0 equiv.), (4-fluoro-2-methoxyphenyl)boronic acid (1.5 equiv.), and PdCl(dppf)-DCM complex (5 mol%) were added and heated at 100 °C for 6 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo. The crude product was triturated with 5% MeOH in MeCN, filtered, and dried. The resulting products were separated by chiral HPLC purification (Method 2) to give the following:

[0352] Compound 31-6 (50 mg) as a solid. LC-MS = 490.5 [M+H] + , retention time = 1.50 min. Chiral HPLC: 99.0%, retention time = 9.80 (Method 2).

[0353] Compound 31-7 (50 mg) as a solid. LC-MS = 490.5 [M+H] + , retention time = 1.50 min. Chiral HPLC: 97.11%, retention time = 16.01 (Method 2).

[0354] [ka] Compound 31 was prepared from compound 31-6 using Boc deprotection procedure B. The reaction mixture was concentrated in vacuo, washed with 5% MeOH in MeCN, and dried to give 40 mg of compound 31 as a solid. 1 H NMR(400MHz,MeOD-d4)δ 8.31(dd,J=8.7,6.5Hz,1H),7.88(s,1H),7.03(dd,J=11.0,2.5Hz,1H),6.84(td,J=8.6,2.5Hz,1H),4.34(t,J=3.2H z,1H),4.12-4.02(m,1H),3.96(s,2H),3.93-3.71(m,4H),3.69-3.51(m,3H),2.02-1.77(m,3H);LC-MS=390.1[M+H] + , retention time = 1.26 min. Chiral HPLC: 94.36%, retention time = 6.43.

[0355] The same procedure was carried out on the second eluting peak, compound 31-7, using Boc deprotection procedure B. The reaction mixture was concentrated in vacuo, washed with 5% MeOH in MeCN, and dried to give 40 mg of compound 31-8 as a solid. 1 H NMR(400MHz,MeOD-d4)δ 8.30(dd,J=8.8,6.5Hz,1H),7.85(s,1H),7.02(dd,J=11.0,2.4Hz,1H),6.83(td,J=8.5,2.5Hz,1H),4.34(t,J=3 .2Hz,1H),4.11-4.02(m,1H),3.96(s,3H),3.93-3.69(m,3H),3.68-3.53(m,2H),2.93(s,1H),2.08-1.71(m,3H); 19 F NMR(376MHz,MeOD-d4)δ -110.24.LC-MS=390.1[M+H] + , retention time = 1.26 min. Chiral HPLC: 98.85%, retention time = 8.16 min.

[0356] The following compounds were prepared by the same route used to prepare compound 31-0 using the appropriate starting materials.

[0357] [Table 44]

[0358] Example 32-0: (4S,4aR,7aR)-6-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydropyrano[2,3-c]pyrrol-4-amine [ka] Compound 32-0 was prepared in the following manner. [ka] tert-Butyl 6-oxa-3-azabicyclo[3.1.0]hexane-3-carboxylate (6.00 g, 32.4 mmol) was combined with copper(I) bromide-dimethylsulfide complex (6.66 g, 32.4 mmol) in anhydrous THF (162 mL). The mixture was cooled to -40 °C. Vinylmagnesium chloride (1.6 M in THF, 81.0 mL, 130 mmol, 4.01 mmol) was added dropwise over 15 min. The mixture was allowed to warm to -10 °C over 4.5 h and then quenched by the addition of saturated aqueous NH4Cl. The reaction mixture was diluted with 400 mL of saturated aqueous NH4Cl, 200 mL of HO was added, and the mixture was stirred vigorously. The mixture was then extracted with EtOAc (3 × 100 mL), and the combined organic layers were washed with saturated aqueous NH4Cl and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was combined with the crude compound from a previous 1 g scale reaction and purified by normal phase chromatography (120 g column) using a running gradient of 0-100% EtOAc / heptane to give 7.59 g of compound 32-1 as an oil. 1H NMR(500MHz,CDCl3)δ 5.70(ddd,J=17.7,10.3,7.9Hz,1H),5.23-5.12(m,2H),4.09(q,J=5.9Hz,1H),3.7 3-3.60(m,2H),3.28-3.16(m,2H),2.73-2.63(m,1H),1.46(s,9H).LC-MS=158.1[M- t Bu+H] + .

[0359] [ka] NaH (60% in mineral oil, 0.844 g, 21.1 mmol) was added to a mixture of compound 32-1 (3.00 g, 14.1 mmol) in DMF (56.3 mL) at 0 °C. After 20 min, allyl bromide (2.43 mL, 28.1 mmol) was added dropwise. The reaction mixture was stirred for 3.5 h, during which time the temperature was allowed to rise to 6 °C. The reaction was quenched by the addition of saturated aqueous NH4Cl (100 mL). The mixture was diluted with HO (200 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (80 g column) using a running gradient of 0–50% EtOAc / heptane to give 3.25 g of compound 32-2 as an oil. 1 H NMR(400MHz,CDCl3)δ 5.89(ddt,J=17.2,10.3,5.6Hz,1H),5.73(ddd,J=17.6,10.4,7.5Hz,1H),5.28(dq,J=17.2,1.7Hz,1H),5.21-5.07(m,3H),4. 07-3.96(m,2H),3.80(q,J=5.1Hz,1H),3.65-3.52(m,2H),3.36-3.16(m,2H),2.86-2.78(m,1H),1.45(s,9H).LC-MS=198.2[M- t Bu+H] + .

[0360] [ka] Compound 32-2 (1.93 g, 7.62 mmol) was dissolved in DCM (152 mL) under N2, and copper(I) iodide (0.073 g, 0.381 mmol) and Grubbs II (0.485 g, 0.571 mmol) were added. The reaction was stirred overnight. The mixture was concentrated in vacuo. The crude material was purified by normal-phase chromatography (80 g column) using a running gradient of 0 to 50% EtOAc / heptane to give 934 mg of compound 32-3 as an oil. 1 H NMR(400MHz,CDCl3)δ 6.01-5.89(m,1H),5.69(dq,J=10.1,2.6Hz,1H),4.44-4.35(m,2H),3.77-3.68(m,1H),3.68-3.5 8(m,2H),3.16-3.07(m,1H),2.93-2.83(m,1H),2.61-2.42(m,1H),1.46(s,9H).LC-MS=170.1[M- t Bu+H] + .

[0361] [ka] A mixture of compound 32-3 (2.75 g, 12.2 mmol) in DCM (122 mL) was treated with mCPBA (6.32 g, 36.6 mmol) at 0 °C and added in four separate equal portions. The mixture was slowly warmed to room temperature and stirred overnight. The mixture was then cooled to 0 °C and poured into saturated aqueous sodium thiosulfate solution (150 mL), also cooled to 0 °C. The mixture was stirred at this temperature for 1.5 h. The mixture was then further diluted with DCM and water. The aqueous layer was extracted once with DCM (100 mL), and the organic layer was washed with saturated aqueous NaHCO and brine, dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (120 g column) using a running gradient of 0–100% EtOAc / heptane to give two fractions.

[0362] Fraction 1 Compound 32-4: rac-tert-butyl (1aR,3aR,6aS,6bS)-hexahydroxyleno[2',3':4,5]pyrano[2,3-c]pyrrole-5(2H)-carboxylate, 911 mg. 1 H NMR(400MHz,CDCl3)δ 4.26(dt,J=13.6,3.0Hz,1H),4.11(ddd,J=13.6,3.3,1.1Hz,1H),3.75-3.54(m,3H),3.49(dd,J=15.4,4.5Hz,1H),3.23(dd,J=4.5,3 .5Hz,1H),3.11(ddd,J=11.9,10.2,8.2Hz,1H),3.03-2.90(m,1H),2.35-2.19(m,1H),1.45(d,J=2.3Hz,9H).LC-MS=186.1[M-tBu+H] + .

[0363] Fraction 2 Compound 32-5: rac-tert-butyl (1aS,3aR,6aS,6bR)-hexahydroxyleno[2',3':4,5]pyrano[2,3-c]pyrrole-5(2H)-carboxylate, 475 mg. 1 H NMR (400 MHz, CDCl3) δ 4.34(dd,J=13.8,1.9Hz,1H),3.99(ddd,J=13.8,5.1,1.7Hz,1H),3.78(ddd,J= 26.2,10.2,8.3Hz,1H),3.67(dd,J=9.9,7.0Hz,1H),3.58(dd,J=9.7,6.9Hz,1H) ,3.42(dd,J=15.9,4.0Hz,1H),3.26(td,J=10.5,6.9Hz,1H),3.14-3.05(m,2H), 3.01(q,J=10.1Hz,1H),2.05-1.89(m,1H),1.48-1.42(m,12H).LC-MS=186.1[M- t Bu+H] + .

[0364] [ka] DIBAL (1 M in PhMe, 2.22 mL, 2.22 mmol) was added dropwise to a mixture of compound 32-4 (268 mg, 1.11 mmol) in DCM (11.1 mL) at −78 °C. The mixture was allowed to warm slowly to 0 °C over 4 h. The reaction was quenched with MeOH (1 mL), and then 1:1 water / Rochelle's salt was added (15 mL). The mixture was stirred for 1 h before being diluted with HO and DCM. The layers were separated, and the aqueous layer was extracted twice with DCM (25 mL). The combined organic layers were washed with brine, dried over MgSO, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (12 g column) using a running gradient of 0–100% EtOAc / heptane to afford 150 mg of compound 32-6 as a colorless foam. 1 H NMR(400MHz,CDCl3-d)δ 4.39-4.21(m,1H),4.02-3.81(m,3H),3.81-3.58(m,1H),3.53-3.33(m,1H),3.16(dd,J=11.7,10.3Hz, 1H),3.02(dt,J=12.7,9.8Hz,1H),2.02-1.83(m,2H),1.82-1.57(m,2H),1.45(s,9H).LC-MS=188.1[M- t Bu+H] + Structure and stereochemistry confirmed by removal of the Boc group (TFA / DCM) by 2D NMR analysis.

[0365] [ka] MsCl (0.072 mL, 0.925 mmol) was added to a mixture of compound 32-6 (150 mg, 0.617 mmol) and EtN (0.258 mL, 1.85 mmol) in DCM (6.17 mL) at 0 °C. The mixture was warmed to room temperature and stirred overnight. Additional EtN (0.086 mL) and MsCl (0.024 mL) were added. The reaction was stirred for 45 min. The reaction mixture was poured into saturated aqueous NHCl and extracted with DCM. The combined organic layers were washed with saturated aqueous NaHCO and brine, then dried over NaSO and concentrated in vacuo. The crude material was purified by normal-phase chromatography (12 g column) using a running gradient of 0–100% EtOAc / heptane to give 96 mg of compound 32-7 as a colorless foam. 1 H NMR(400MHz,CDCl3)δ 5.24-5.14(m,1H),4.04-3.80(m,3H),3.81-3.65(m,1H),3.62-3.47(m, 1H),3.15-2.99(m,5H),2.16-1.92(m,3H),1.45(s,9H).LC-MS=266.1[M- t Bu+H] + .

[0366] [ka] NaN (199 mg, 3.07 mmol) was added to a mixture of compound 32-7 (493 mg, 1.53 mmol) in DMF (15.3 mL), and the resulting mixture was heated to 85 °C for 1.5 h. The mixture was diluted with HO (50.0 mL) and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated aqueous NaHCO and brine, then dried over MgSO and concentrated in vacuo. The crude material was purified by normal-phase chromatography (24 g column) using a running gradient of 0 to 100% EtOAc / heptane to give 284 mg of compound 32-8 as an oil. 1H NMR(400MHz,CDCl3)δ 4.16(dt,J=11.6,5.6Hz,1H),3.88-3.66(m,2H),3.65-3.55(m,1H),3.45-3.34(m,2H),3.12(q,J=10. 2Hz,1H),3.01(t,J=11.0Hz,1H),2.05-1.95(m,1H),1.93-1.66(m,2H),1.46(s,9H).LC-MS=213.2[M- t Bu+H] + .

[0367] [ka] A solution of compound 32-8 (300 mg, 1.118 mmol) in anhydrous DCM (5.6 mL) was treated with 4 M HCl in dioxane (3 mL, 12.00 mmol) at room temperature for 1 h. The mixture was concentrated in vacuo and dried under high vacuum to give compound 32-9 as a brown residue, which was used in the next step without further purification.

[0368] [ka] To a suspension of compound 32-9 (229 mg, 1.119 mmol) and compound 1 (351 mg, 1.063 mmol) in anhydrous MeCN (5.6 mL) was added DIPEA (1.173 mL, 6.71 mmol). The reaction was heated to 80 °C for 3 h. The reaction was concentrated in vacuo. The crude product was purified by normal phase chromatography (12 g column) using a running gradient of 0 to 40% (5:95 MeOH:EtOAc) / heptane to give 338 mg of compound 32-10 as a solid.

[0369] [ka] Compound 32-10 (338 mg, 0.810 mmol), PdCl(dppf)-DCM complex (99 mg, 0.122 mmol), (2-methoxy-6-methylpyridin-3-yl)boronic acid (316 mg, 1.620 mmol), and KPO (516 mg, 2.430 mmol) were suspended in dioxane (6751 μL) and HO (1350 μL). Argon was sparged into the resulting suspension for 15 minutes, and the reaction was heated to 80 °C overnight. The reaction mixture was diluted with EtOAc and HO, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO, filtered, and concentrated. The crude material was purified by normal-phase chromatography (12 g column) using a running gradient of 0-40% (5:95 MeOH:EtOAc) / heptane to give 206 mg of a mixture of compounds 32-11 and 32-12 as a solid. Chiral separation was performed using (Method 7) to give 77.4 mg of the first eluting peak compound 32-11 (100%; retention time 1.89 min) and 79.8 mg of the second eluting peak compound 32-12 (99.23%; 3.03 min). Relative stereochemistry known, absolute stereochemistry unknown. LC-MS=441.1 [M+H] + .

[0370] [ka] A suspension of the first-eluting compound 32-11 (77.4 mg, 0.176 mmol) and Ph3P (92 mg, 0.351 mmol) in 10:1 THF / HO (1500 μL) was stirred overnight at room temperature. The crude material was purified by preparative HPLC to give 35.2 mg of compound 32. 1H NMR(400MHz,DMSO-d6)δ 8.53(d,J=7.7Hz,1H),8.09(s,3H),7.60(s,1H),6.97(d,J=7.8Hz,1H),4.10(dd,J=11.7,5.0 Hz,1H),4.01(s,3H),3.83(ddd,J=11.2,7.5,2.8Hz,2H),3.76(dd,J=9.7,7.4Hz,1H),3.66-3 .56(m,1H),3.51-3.39(m,1H),3.40-3.31(m,2H),2.98(p,J=6.9Hz,1H),2.14-2.02(m,1H),1 .97(d,J=13.0Hz,1H),1.63(qd,J=12.6,5.4Hz,1H),1.27(d,J=6.9Hz,6H).LC-MS=415.2[M+H] + .

[0371] [ka] The same procedure as for compound 32 is carried out on the second eluting peak, compound 32-12, to give compound 32-13 as a single compound of unknown absolute stereochemistry. 1 H NMR(400MHz,DMSO-d6)δ 8.53(d,J=7.7Hz,1H),8.08(s,3H),7.60(s,1H),6.97(d,J=7.8Hz,1H),4.11(dd,J=11.7 ,5.0Hz,1H),4.01(s,3H),3.87-3.82(m,2H),3.76(dd,J=9.7,7.4Hz,1H),3.65-3.57(m,1 H),3.51-3.40(m,1H),3.40-3.29(m,2H),2.98(p,J=6.9Hz,1H),2.14-2.02(m,1H),1.97( d,J=12.8Hz,1H),1.63(qd,J=12.6,5.3Hz,1H),1.27(d,J=6.9Hz,6H).LC-MS=415.2[M+H] + .

[0372] Example 33-0: (3aS,5R,7R,7aR)-7-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol [ka] Compound 33-0 was prepared in the following manner. [ka] (Z)-4-Methoxybut-3-en-2-one (5 g, 50 mmol) was dissolved in anhydrous THF (25 mL). Dibenzylamine (19.7 g, 100 mmol) in anhydrous THF (40 mL) was added dropwise, and the reaction mixture was stirred at room temperature for 16 h. The mixture was quenched with HO and extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 20–45% EtOAc / n-hexane to afford 10 g of compound 33-1 as a pale orange gum. 1 H NMR(400MHz,CDCl3)δ 7.89(d,J=12.8Hz,1H),7.41-7.20(m,10H),5.37(d,J=12.8Hz,1H),4.37(br s,4H),2.15(s,3H).LC-MS=266.42[M+H] + .

[0373] [ka] KHMDS (0.5 M in PhMe, 9.01 g, 45.3 mmol) was added to anhydrous THF (95 mL) at −78° C. under a N atmosphere. A solution of compound 33-1 (10.0 g, 37.73 mmol) in anhydrous THF (100 mL) was added over 15 min. The reaction was slowly warmed to −50° C. and stirred for 2 h. The reaction was cooled to −78° C., and a solution of TBSCl (7.40 g, 49.1 mmol) in anhydrous THF (75 mL) was added dropwise over 10 min. The resulting mixture was warmed to 0° C. over 2.5 h, then poured into EtO and filtered through a pad of CELITE. The filtrate was concentrated in vacuo to give 11.8 g of compound 33-2, which was used immediately in the next step without further purification.

[0374] [ka] Compound 33-2 (11.8 g, 31.1 mmol) was dissolved in anhydrous PhMe (100 mL) and cooled to −78 °C under N. A solution of N-benzylmaleimide (5.24 g, 28.0 mmol) in anhydrous PhMe (75 mL) was added dropwise, and the reaction was allowed to slowly cool to room temperature and stirred for 16 h. The mixture was quenched with HO and extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo to give a crude residue, which was purified by normal-phase chromatography (basic alumina) using a running gradient of 3–12% EtOAc / n-hexane to give 5 g of compound 33-3. 1 H NMR(400MHz,CDCl3)δ 7.43-7.25(m,15H),4.92-4.91(m,1H),4.72-4.63(m,1H),4.48-4.44(m,1H),3.95-3.92(m,1H),3.86-3.76(m,2H),3.67-3.61(m,2 H),3.30-3.25(m,1H),3.15-3.10(m,1H),2.72-2.67(m,1H),2.32-2.25(m,1H),0.89(s,9H),0.14-0.10(m,6H).LC-MS=567.45[M+H] + .

[0375] [ka] Compound 33-3 (5 g, 8.84 mmol) was dissolved in i-PrOH (50 mL), and then 10% Pd / C (2.50 g) was added. The reaction was stirred at room temperature under 1 atm of H for 30 h. The mixture was filtered through a CELITE pad, and the pad was washed with EtOAc. The filtrate was concentrated in vacuo to give 3.03 g of compound 33-4, which was used in the next step without further purification. LC-MS=389.25 [M+H] + .

[0376] [ka] Compound 33-4 (3.03 g, 7.73 mmol) was dissolved in DCM (30 mL) and EtN (2.34 g, 23.2 mmol) was added. The reaction was stirred at room temperature for 15 min. Then, a solution of (Boc)O (1.87 g, 8.59 mmol) in DCM (5 mL) was added dropwise at 0 °C. The mixture was concentrated in vacuo, then diluted with EtOAc and washed successively with water, 5% citric acid solution, and saturated NaHCO. The organic layer was dried over NaSO and concentrated in vacuo. The crude material was purified by normal-phase chromatography (basic alumina) using a running gradient of 8–22% EtOAc / n-hexane to give 1.20 g of compound 33-5. 1 H NMR(400MHz,CDCl3)δ 7.41-7.32(m,5H),6.19(d,J=9.2Hz,1H),4.70-4.59(m,1H),4.08-4.03(m,1H),3.10-3 .01(m,1H),2.33-2.26(m,1H),2.09-1.99(m,1H),1.83-1.77(m,1H),1.43(s,9H),1.30 -1.26(m,1H),0.89(s,9H),0.14-0.10(m,6H).LC-MS=487.35[MH] - .

[0377] [ka] Compound 33-5 (0.690 g, 1.41 mmol) was dissolved in anhydrous PhMe (15 mL) and cooled to -78 °C. Red-Al (5.71 g, 28.5 mmol, 70% in PhMe) was added, and the reaction mixture was stirred at room temperature for 1 h. The mixture was cooled to 0 °C, and HO (2.75 mL) was added, followed by a mixture of 1 N NaOH (3 mL) and HO (3 mL). The mixture was then diluted with EtOAc (25 mL) and filtered through a CELITE pad. The filtrate was dried over NaSO and concentrated in vacuo to give 0.730 g of compound 33-6, which was used in the next step without further purification. LC-MS = 461.61 [M+H] + .

[0378] [ka] Compound 33-6 (0.730 g, 1.58 mmol) was dissolved in i-PrOH (15 mL), and then 10% Pd / C (0.350 g) was added. The reaction mixture was stirred at room temperature under 1 atmosphere of H for 16 hours. The mixture was filtered through a CELITE pad and concentrated in vacuo to give 0.550 g of compound 33-7 as a racemic mixture, which was used in the next step without further purification. LC-MS=371.49 [M+H] + .

[0379] [ka] To a suspension of compound 1 and compound 33-7 in anhydrous MeCN (3 mL) was added DIPEA (0.635 mL, 3.64 mmol). The reaction was heated to 100 °C for 10 h. The reaction mixture was washed with DCM and concentrated in vacuo. The crude material was purified by normal phase chromatography (40 g column) using a running gradient of 0-30% (3:1 EtOAc:EtOH) / heptane to give 150 mg of compound 33-8 as a solid. LC-MS = 620.5 [M+H] + .

[0380] [ka] A mixture of PdCl(dppf)-DCM complex (9.88 mg, 0.012 mmol), compound 33-8 (75 mg, 0.121 mmol), and KPO (0.182 mL, 0.363 mmol) in dioxane (3 mL) and HO (0.6 mL) was sparged with N for 5 min. After degassing, the suspension was stirred at 80 °C for 3 h. The reaction mixture was diluted with DCM and extracted twice with water. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The reaction mixture was purified by normal-phase chromatography (12 g column) using a running gradient of 0–70% EtOAc / DCM to give 40 mg of compound 33-9. LC-MS = 643.7 [M+H] + .

[0381] [ka] To a solution of compound 33-9 (40 mg, 0.062 mmol) in DCM (4 mL) was added 4 M HCl (0.016 mL, 0.062 mmol), and the resulting suspension was stirred at room temperature for 1 h. The crude product was concentrated in vacuo and purified by preparative HPLC to give 9.5 mg of compound 33. 1 H NMR(400MHz,DMSO-d6)δ 8.54(d,J=7.7Hz,1H),8.00(s,3H),7.61(s,1H),6.96(d,J=7.7Hz,1H),4.01(s,3H), 3.68(dd,J=9.7,5.3Hz,1H),3.52(dq,J=18.0,10.1Hz,4H),3.35(d,J=9.8Hz,1H),2. 98(p,J=6.8Hz,1H),2.77(s,1H),1.97(d,J=11.9Hz,1H),1.85(d,J=12.6Hz,1H),1.4 5(q,J=12.1Hz,1H),1.27(d,J=6.8Hz,7H),1.08(q,J=12.2Hz,1H).LC-MS=429.4[M+H] + .

[0382] Example 34-0: (3aR,4S,5S,7aS)-4-amino-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol [ka] Compound 34-0 was prepared in the following manner. [ka] A mixture of N-benzylmaleimide (5.53 g, 29.5 mmol) and tert-butyl (E)-buta-1,3-dien-1-ylcarbamate (5 g, 29.5 mmol) in anhydrous dioxane (148 mL) was heated to reflux for 16 h. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The crude residue was dissolved in a minimal amount of DCM, applied to the top of a solid-packed cartridge, and purified by normal-phase chromatography (120 g column) using a running gradient of 0–30% EtOAc / heptane to afford 10 g of compound 34-1 as a white foam. 1 H NMR(500MHz,CDCl3)δ 7.42-7.14(m,5H),6.25(d,J=9.4Hz,1H),5.89-5.75(m,2H),4.59(s,2H),4.50-4.35(m,1H),3.23(dd,J=9. 0,6.1Hz,1H),3.20-3.09(m,1H),2.76-2.59(m,1H),2.26-2.14(m,1H),1.46(s,9H).LC-MS=257.2[M-Boc+H] + .

[0383] [ka] Compound 34-1 (2.91 g, 8.16 mmol) was sparged with N2 and anhydrous PhMe (100 mL) was added to obtain a homogeneous solution. Red-Al (60% in PhMe, 13.3 mL, 40.8 mmol) was then added dropwise at -78 °C. The reaction became extremely viscous and could not be stirred properly due to the thick gel. The reaction was allowed to warm to room temperature, at which point stirring was resumed. After 1.5 h, the reaction was cooled to -78 °C and carefully quenched by the dropwise addition of MeOH (5 mL). Once all effervescence had ceased, the reaction was allowed to warm to room temperature and an aqueous solution of Rochelle's salt was added. The resulting layers were separated, and the aqueous layer was extracted three times with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal phase chromatography (40 g column) using a running gradient of 0-40% EtOAc / heptane to give 1.73 g of compound 34-2 as a solid. 1 H NMR(400MHz,CDCl3)δ 7.36-7.20(m,5H),5.85(dddd,J=9.4,5.7,3.9,2.0Hz,1H),5.74(d,J=9.9Hz,1H),5.31(d ,J=7.3Hz,1H),4.23(s,1H),3.60(d,J=3.3Hz,2H),2.85(dd,J=9.0,7.6Hz,1H),2.74(ddt ,J=19.8,15.7,7.4Hz,2H),2.56(dtd,J=11.7,8.7,5.8Hz,1H),2.36(t,J=7.8Hz,1H),2.2 4(t,J=7.8Hz,1H),2.18-2.06(m,1H),2.02-1.90(m,1H),1.44(s,9H).LC-MS=329.4[M+H] + .

[0384] [ka] Compound 34-2 (2.07 g, 6.30 mmol) was flushed with N and dissolved in anhydrous DCM (63.0 mL). Cbz-Cl (1.80 mL, 12.6 mmol) was added dropwise at room temperature, and the reaction was stirred for 6 h. It was then quenched with NaHCO and stirred for 15 min. The layers were separated, and the aqueous layer was extracted twice with DCM. The combined organics were dried over MgSO, filtered, and concentrated. The crude residue was purified by normal-phase chromatography (40 g column) using a running gradient of 0–100% EtOAc / heptane to give 1.54 g of compound 34-3 as a solid. 1 H NMR(400MHz,CDCl3)δ 7.45-7.27(m,4H),5.74(ddt,J=10.0,5.0,2.5Hz,1H),5.44(dt,J=10.2,2.6Hz,1H) ,5.23-5.02(m,2H),4.53(s,1H),4.43(dd,J=18.7,8.6Hz,1H),3.61-3.26(m,3H),3. 15(dt,J=10.6,9.3Hz,1H),2.84(s,1H),2.42(ddt,J=13.5,9.2,5.0Hz,1H),2.31-2 .10(m,1H),1.83(ddq,J=18.8,9.4,3.2Hz,1H),1.44(s,9H).LC-MS=273.3[M-Boc+H] + .

[0385] [ka] Compound 34-3 (117 mg, 0.314 mmol) was sparged with N and then dissolved in anhydrous THF (10 mL). The solution was cooled to 0 °C, and borane tetrahydrofuran complex (0.628 mL, 0.628 mmol) was added dropwise over 1 h. Further borane tetrahydrofuran complex (0.628 mL, 0.628 mmol) was added. After 5 h, the reaction was cooled to 0 °C, and the excess borane was carefully quenched with HO (10 mL), followed by sodium perborate monohydrate (267 mg, 2.67 mmol). The reaction was stirred overnight at room temperature. The reaction was diluted with HO and EtOAc and then filtered. The resulting filtrate was extracted three times with EtOAc, and the combined organic layers were dried over MgSO, filtered, and concentrated. The crude residue was purified by normal phase chromatography (12 g) using a running gradient of 0-60% EtOAc / heptane to give 99.7 mg of compound 34-4 as an oil. LC-MS=291.3 [M+H] + .

[0386] [ka] A mixture of compound 34-4 (95 mg, 0.243 mmol) and 10% Pd / C (78 mg, 0.073 mmol) was purged with N. EtOAc (4.8 mL) and AcOH (20 μL, 0.349 mmol) were added. The reaction was placed under H and stirred at room temperature for 4.5 h. The reaction was purged with argon, diluted with MeOH, and filtered through a pad of CELITE. The CELITE was thoroughly washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo. The crude residue, compound 34-5, was carried on to the next step without further characterization or purification.

[0387] [ka] To a suspension of compound 34-5 (84.5 mg, 0.330 mmol) and compound 1 (103 mg, 0.313 mmol) in anhydrous MeCN (3.3 mL) was added DIPEA (173 μL, 0.989 mmol). The reaction mixture was heated to 100 °C for 2 h. The reaction mixture was concentrated in vacuo. The crude residue was purified by normal phase chromatography (12 g column) using a running gradient of 0 to 60% (5% MeOH: EtOAc) / heptane to give 86.8 mg of compound 34-6 as a solid. 1 H NMR (500 MHz, CDCl3) δ 7.13(t,J=1.3Hz,1H),4.83(d,J=6.8Hz,1H),3.74(d,J=10.5Hz,1H),3.69-3.5 8(m,3H),3.44(t,J=10.6Hz,1H),3.32(d,J=9.8Hz,1H),3.18(d,J=10.3Hz,1H) ,2.61(s,1H),2.43(dq,J=11.3,5.6Hz,1H),2.16-2.08(m,1H),1.80(dd,J=14. 8,4.7Hz,1H),1.71(s,1H),1.49(s,9H),1.42-1.33(m,1H).LC-MS=506.4[M+H] + .

[0388] [ka] Compound 34-6 (84 mg, 0.166 mmol), PdCl(dppf)-DCM complex (20.36 mg, 0.025 mmol), (2-methoxy-6-methylpyridin-3-yl)boronic acid (64.8 mg, 0.332 mmol), and KPO (106 mg, 0.499 mmol) were suspended in dioxane (1.4 mL) and HO (0.3 mL). After degassing with argon for 15 min, the reaction mixture was heated to 80 °C for 2.5 h. The reaction mixture was diluted with DCM and extracted twice with the aqueous layer. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase chromatography (12 g column) using a running gradient of 0–50% (5% MeOH: EtOAc) / heptane to give 49.3 mg of compound 34-7. LC-MS = 529.6 [M+H] +.

[0389] [ka] Compound 34-7 (48.3 mg, 0.091 mmol) was dissolved in anhydrous DCM (2 mL) and TFA (352 μL, 4.57 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 40.8 mg of compound 34. 1 H NMR(400MHz,DMSO-d6)δ 8.54(d,J=7.7Hz,1H),8.16-7.92(m,3H),7.62(s,1H),6.96(d,J=7.7Hz,1H),4.01(s,3H), 3.66(ddd,J=15.6,9.8,5.0Hz,2H),3.54(d,J=10.1Hz,2H),3.30(d,J=9.8Hz,1H),3.27-3. 16(m,1H),2.94(ddt,J=26.4,10.0,5.8Hz,2H),2.46(q,J=5.6Hz,1H),1.88(d,J=8.5Hz,1H ),1.71(d,J=11.2Hz,1H),1.36(t,J=10.8Hz,2H),1.27(d,J=7.6Hz,6H).LC-MS=429.2[M+H] + .

[0390] Example 35-0: (3aR,4S,5R,7aS)-4-amino-2-(5-(2-methoxy-6-methylpyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)octahydro-1H-isoindol-5-ol [ka] Compound 35-0 was prepared starting from compound 34-4 in the following manner. [ka] A mixture of compound 34-4 (1.14 g, 2.92 mmol), 4-nitrobenzoic acid (0.732 g, 4.38 mmol), and Ph3P (1.149 g, 4.38 mmol) was suspended in anhydrous THF (60.0 mL) under N2. DEAD (0.690 mL, 4.38 mmol) was then added at 0 °C. The reaction was stirred at 0 °C for 5 min and then warmed to room temperature over 15 min. After that, the reaction was heated to 70 °C for 16 h. The reaction mixture was concentrated in vacuo and purified by normal-phase chromatography (80 g column) using a running gradient of 0–30% EtOAc / heptane to give 1.65 g of the desired intermediate as a solid. 1 H NMR showed an inseparable 3:1 mixture of the desired product and diethylhydrazine-1,2-dicarboxylate, respectively. 1 H NMR(500MHz,CDCl3)δ 8.32(d,J=8.5Hz,1H),8.16(d,J=8.5Hz,1H),8.14-8.01(m,2H),7.45-7.28(m,5H),5.42( s,1H),5.31-5.10(m,1H),5.16(d,J=2.1Hz,1H),4.80-4.68(m,1H),4.13(s,1H),3.79(t, J=11.2Hz,1H),3.72-3.57(m,1H),3.55-3.33(m,2H),2.85(s,1H),2.37-2.30(m,1H),2.2 5-2.16(m,1H),1.77-1.64(m,1H),1.55-1.49(m,2H),1.42(s,9H).LC-MS=440.4[M-Boc+H] + The resulting intermediate (820 mg, 1.52 mmol) and K2CO3 (6.15 g, 44.5 mmol) were suspended in MeOH (15.2 mL), and the reaction mixture was stirred at room temperature for 2 h. The reaction was quenched with NH4Cl, diluted with EtOAc, and the layers were separated. The aqueous layer was extracted, and the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by normal-phase chromatography (24 g column) using a running gradient of 0–40% EtOAc / heptane to afford 748 mg of compound 35-1 as a solid. 1 H NMR showed an inseparable mixture of the desired product and dimethyl / diethylhydrazine-1,2-dicarboxylate.1 H NMR(500MHz,CDCl3)δ 7.40-7.31(m,4H),7.29(t,J=5.1Hz,1H),5.31-5.20(m,1H),5.18-5.02( m,2H),4.00(s,1H),3.90-3.71(m,2H),3.55-3.26(m,3H),2.78-2.62(m, 1H),2.20-2.09(m,1H),1.91-1.77(m,1H),1.63(q,J=12.8Hz,1H),1.54( q,J=12.8Hz,1H),1.42(s,9H),1.38-1.32(m,1H).LC-MS=291.3[M-Boc+H] + .

[0391] [ka] Compound 35-1 (347 mg, 0.889 mmol) and 10% Pd / C (284 mg, 0.267 mmol) were placed under N. Then, EtOAc (15.4 mL) and AcOH (0.051 mL, 0.889 mmol) were added. The reaction was stirred under H at room temperature for 1 h. The reaction was diluted with MeOH and filtered through a pad of CELITE. The CELITE pad was thoroughly washed with MeOH and EtOAc, and the filtrate was concentrated in vacuo to give compound 35-2.

[0392] [ka] Compound 35-2 (223 mg, 0.870 mmol) and compound 1 (273 mg, 0.826 mmol) were suspended in anhydrous MeCN (5 mL), and then DIPEA (0.456 mL, 2.61 mmol) was added. The reaction was heated to 100 °C for 2 h. The reaction was concentrated in vacuo. The crude material was purified by normal phase chromatography (40 g column) using a running gradient of 0 to 30% (3:1 EtOAc / EtOH) / heptane to give 326 mg of compound 35-3 as a solid. 1H NMR(500MHz,CDCl3)δ 7.09(s,1H),5.26(d,J=7.1Hz,1H),4.12(s,1H),4.00(t,J=10.3Hz,1H),3.94-3.81(m,1H),3.60(dd,J=9.6,5.5Hz,1H),3.49(t,J=9.1Hz,1H) ,3.37(d,J=10.1Hz,1H),2.99-2.82(m,1H),2.35(d,J=10.5Hz,1H),2.0 1-1.83(m,2H),1.75-1.60(m,2H),1.50(d,J=14.2Hz,1H),1.47(s,9H).

[0393] [ka] To a mixture of PdCl(dppf)-DCM complex (24.97 mg, 0.031 mmol), (2-methoxy-6-methylpyridin-3-yl)boronic acid (68.1 mg, 0.408 mmol), and KPO (130 mg, 0.611 mmol) was added a solution of compound 35-3 (103 mg, 0.204 mmol) in dioxane (1.7 mL) and HO (0.34 mL). The reaction was heated to 80 °C for 2.5 h. The reaction mixture was diluted with DCM and extracted twice with water. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude reaction was purified by normal-phase chromatography (12 g column) using a running gradient of 0–50% (2% MeOH / EtOAc) / DCM to give 77 mg of compound 35-4. LC-MS = 501.5 [M-Boc+H] + .

[0394] [ka] A solution of compound 35-4 (76.7 mg, 0.153 mmol) in DCM (3 mL) was treated with TFA (590 μL, 7.66 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified twice by preparative HPLC to give 9.9 mg of compound 35. 1H NMR(500MHz,DMSO-d6)δ 8.59(d,J=7.7Hz,1H),7.57(s,1H),6.99(d,J=7.7Hz,1H),4.89(s,1H),4.00(s,3H),3.95(t,J=10.0Hz,1H),3.80(s,1H),3.61(dd,J=9.7, 5.8Hz,1H),3.51(t,J=8.6Hz,1H),3.02(s,1H),2.62(s,1H),2.45(s,3H),2.34(s,1H),1.78(s,1H),1.61-1.39(m,3H).LC-MS=401.2[M+H] + .

[0395] The following compounds were prepared by the same route used to prepare compound 35-0.

[0396] [Table 45]

[0397] Example 36-0: (3aR,4R,7aS)-2-(5-(6-isopropyl-2-methoxypyridin-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-2-yl)-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-amine [ka] Compound 36-0 was prepared in the following manner. [ka] Compound 34-2 (1.04 g, 3.17 mmol) was dissolved in anhydrous DCM (30 mL), and then Alloc-Cl (0.650 mL, 6.12 mmol) was added dropwise. The reaction was stirred at room temperature for 6 h, then quenched with aqueous NaHCO and stirred overnight. The layers were then separated, and the aqueous layer was extracted with DCM. The combined organic layers were dried over MgSO, filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (24 g column) using a running gradient of 10–30% EtOAc / heptane to give 0.732 g of compound 36-1 as a solid. 1 H NMR(500MHz,CDCl3)δ 5.92(ddq,J=16.7,11.2,5.8Hz,1H),5.73(ddp,J=10.4,5.1,2.5Hz,1H),5.43(d,J =10.3Hz,1H),5.28(dd,J=17.4,5.3Hz,1H),5.18(dd,J=10.4,6.8Hz,1H),4.57(br s,2H),4.52(br s,2H),3.56-3.42(m,1H),3.42-3.25(m,2H),3.13(t,J=10.9Hz,1H),2.82(dt,J=13.1,6.4Hz,1H),2.40(t q,J=9.2,4.6Hz,1H),2.18(dq,J=18.9,6.7Hz,1H),1.85-1.74(m,1H),1.42(s,9H).LC-MS=223.2[M-Boc+H] + .

[0398] [ka] Compound 36-1 (725 mg, 2.25 mmol) was dissolved in anhydrous DCM (22.5 mL), and then phenylsilane (0.832 mL, 6.75 mmol) and Pd(PPh3)4 (260 mg, 0.225 mmol) were added. The reaction was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated in vacuo to give compound 36-2, which was used in the next step without further purification. LC-MS=239.3 [M+H] + .

[0399] [ka] Compound 36-2 (181 mg, 0.759 mmol) and compound 1 (238 mg, 0.721 mmol) were suspended in anhydrous MeCN (5 mL), and then DIPEA (0.4 mL, 2.278 mmol) was added. The reaction was heated to 100 °C overnight. The reaction mixture was concentrated in vacuo and purified by normal phase chromatography (12 g column) using a running gradient of 0 to 30% (5% MeOH / EtOAc) / heptane to give 74 mg of compound 36-3 as a solid. LC-MS = 488.3 [M+H] + .

[0400] [ka] Compound 36-3 (73 mg, 0.150 mmol), PdCl(dppf)-DCM complex (18.35 mg, 0.022 mmol), (2-methoxy-6-methylpyridin-3-yl)boronic acid (58.4 mg, 0.300 mmol), and KPO (95 mg, 0.449 mmol) were dissolved in dioxane (1.2 mL) and HO (0.250 mL). The reaction was heated to 80 °C for 2.5 h. The reaction mixture was diluted with EtOAc and extracted with water. The combined organic layers were filtered over NaSO and concentrated. The crude residue was purified by normal-phase chromatography (4 g column) using a running gradient of 0–40% (5% MeOH / EtOAc) / heptane to give 60 mg of compound 36-4 as a solid. LC-MS = 511.5 [M+H] + .

[0401] [ka] A solution of compound 36-4 (60 mg, 0.117 mmol) in DCM (1.2 mL) was treated with TFA (453 μL, 5.87 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and purified by preparative HPLC to give 47.6 mg of compound 36. 1H NMR(500MHz,DMSO-d6)δ 8.56(d,J=7.7Hz,1H),8.17(d,J=5.7Hz,3H),7.64(s,1H),6.97(d,J=7.7Hz,1H),5.94(ddt,J=10.2,5 .0,2.6Hz,1H),5.59(d,J=10.4Hz,1H),4.26(s,1H),4.02(s,3H),3.68(dd,J=9.6,4.7Hz,1H),3.60(t, J=8.8Hz,1H),3.40(dd,J=11.6,9.7Hz,2H),2.99(p,J=6.9Hz,1H),2.91(dt,J=12.1,6.0Hz,1H),2.70( tt,J=9.1,4.7Hz,1H),2.39-2.31(m,1H),1.92-1.80(m,1H),1.28(d,J=6.9Hz,6H).LC-MS=411.2[M+H] + .

[0402] Example 37-0: 2-(4-chloro-5-fluoro-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 37-0 was prepared in the following manner. [ka] To a stirred solution of 2-chloro-1-fluoro-4-methoxybenzene (1.8 g, 9.34 mmol) in CHCl (70 mL) was added silver trifluoroacetate (7.42 g, 33.62 mmol), followed by I (4.98 g, 19.61 mmol). The resulting solution was stirred at room temperature for 2 h. The reaction mixture was filtered through a pad of CELITE, and the filtrate was extracted with EtOAc (100 mL × 2), and the HO was washed with brine. The combined organic layers were dried over NaSO, filtered, and evaporated in vacuo. The crude compound was purified by normal phase chromatography to give 2.2 g of compound 37-1 as a pale pink liquid. 1H NMR (400MHz, DMSO-d6) δ 7.87 (d, J = 8.5 Hz, 1H), 7.21 (d, J = 6.4 Hz, 1H), 3.83 (s, 3H); HPLC: 97.99%, retention time = 7.351 minutes.

[0403] [ka] A solution of compound 37-1 (1.8 g, 6.28 mmol) in THF (20 mL) was cooled to -40 °C under an argon atmosphere. Next, iPrMgCl·LiCl solution (9.6 mL, 1.3 M in THF, 12.56 mmol) was added. The resulting mixture was stirred at -40 °C for 2 h. Next, 2-methoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.5 g, 15.70 mmol) was added at -40 °C. The resulting solution was stirred at room temperature for 16 h. The reaction was concentrated in vacuo, and the crude product was purified by normal-phase chromatography using a running gradient of 5–10% EtOAc / n-hexane to give 700 mg of compound 37 as a colorless liquid. 1 H NMR(300MHz, CDCl3)δ 7.43(dd,J=9.1,1.1Hz,1H),6.85(dd,J=5.6,1.1Hz,1H),3.80(s,3H),1.34(s,12H);HPLC:65.21%, retention time=6.274 minutes.

[0404] Example 38-0: (2-Isopropoxy-6-isopropylpyridin-3-yl)boronic acid [ka] Compound 38-0 was prepared in the following manner. [ka] A mixture of allylpalladium chloride dimer (9.09 mg, 0.025 mmol), RockPhos (34.9 mg, 0.075 mmol), and cesium carbonate (2428 mg, 7.45 mmol) was flushed with argon for several minutes, then anhydrous PhMe (5 mL) was added, followed by IPA (0.76 mL, 9.94 mmol). The reaction was heated to 90 °C for 3 minutes, then 2-bromo-6-isopropylpyridine (0.71 mL, 4.97 mmol) was added, and the reaction was continued at 90 °C for 1 hour. The mixture was filtered through a pad of CELITE, concentrated in vacuo, and then purified by normal-phase chromatography (80 g column) using a running gradient of 0–10% EtOAc / heptane to give 519 mg of compound 38-1 as an oil. LC-MS = 180.2 [M+H] + .

[0405] [ka] A solution of compound 38-1 (519 mg, 2.90 mmol), TMEDA (0.52 mL, 3.45 mmol), and anhydrous EtO (6 mL) was placed under a N atmosphere and cooled to -78 °C. n-BuLi (2.7 mL, 4.32 mmol) (1.6 M in hexanes) was then added dropwise over several minutes. The reaction turned brown and was allowed to warm to room temperature over 1 h, where it slowly turned dark red-brown. The reaction was cooled to -78 °C and B(O i Pr)3 (2 mL, 8.61 mmol) was added dropwise over several minutes. The reaction was allowed to warm to room temperature over 1 h. The reaction was quenched with 6 M HCl (2 mL), and then the mixture was basified with 2 M NaOH (1 mL) to adjust the pH to 7. The reaction was then acidified again with 1 M HCl to a pH of approximately 4, stirred vigorously at room temperature for 30 min, and then extracted with EtOAc. The resulting organic layer was dried over Na2SO4, concentrated in vacuo, and purified by normal phase chromatography (80 g column) using a running gradient of 0–20% (3:1 EtOAc:EtOH) / heptane to afford 300.6 mg of compound 38 as a pale yellow gum. 1H NMR(500MHz,DMSO-d6)δ 7.85(d,J=7.2Hz,1H),7.65(s,2H),6.82(dd,J=7.3,0.4Hz,1H),5.33(p,J=6. 2Hz,1H),2.90(h,J=6.7Hz,1H),1.33(d,J=6.2Hz,6H),1.20(d,J=6.8Hz,6H).

[0406] Example 39-0: (2-ethoxy-6-isopropylpyridin-3-yl)boronic acid [ka] Compound 39-0 was prepared in the following manner. [ka] A solution of 2-chloro-6-ethoxypyridine (4.20 mL, 31.7 mmol), anhydrous THF (110 mL), and anhydrous NMP (15 mL) was placed under a N atmosphere and iron(III) acetylacetonate (0.672 g, 1.904 mmol) was added. The flask was cooled to -40 °C, and then i-PrMgCl (24 mL, 48.0 mmol) was added over several minutes. The reaction mixture immediately turned dark brown and was warmed to 0 °C for 1 h. The reaction was quenched with aqueous NH4Cl (150 mL), extracted twice with EtOAc, and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by normal-phase chromatography (330 g column) using a running gradient of 0–5% EtOAc / heptane to give 2.5 g of compound 39-1 as an oil.

[0407] [ka] A solution of compound 39-1 (500 mg, 3.03 mmol), TMEDA (0.46 mL, 3.05 mmol), and anhydrous EtO (6 mL) was placed under a N atmosphere and cooled to -78 °C. n-BuLi (2.3 mL, 3.68 mmol) (1.6 M in hexanes) was added dropwise over several minutes. The reaction turned deep orange and was allowed to warm to room temperature over 30 minutes. The reaction was cooled to -78 °C and B(O i Pr)3 (1.5 mL, 6.46 mmol) was added dropwise over several minutes. The reaction mixture was allowed to warm to room temperature over 30 minutes. No orange color appeared to be released, so the reaction was cooled again to -78 °C and additional B(O i Pr)3 (2 mL, 8.61 mmol) was added. The reaction was allowed to warm to room temperature and stirred for 30 minutes, at which point the reaction still appeared red-orange. The reaction was cooled again to -78 °C and further B(O i Pr)3 (1 mL, 4.31 mmol) was added, warmed to room temperature, and stirred for 17 h. The reaction was quenched with 6 M HCl and then acidified to approximately pH 4 with 1 M HCl. The biphasic mixture was stirred vigorously at room temperature for 30 min, then extracted with EtOAc, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by normal phase chromatography (120 g column) using a running gradient of 0–10% (3:1 EtOAc:EtOH) / heptane to afford 497 mg of compound 39. 1 H NMR(400MHz,DMSO-d6)δ 7.84(d,J=7.2Hz,1H),7.68(s,2H),6.82(dd,J=7.2,0.4Hz,1H),4.38(q,J= 7.0Hz,2H),2.89(p,J=6.8Hz,1H),1.33(t,J=7.0Hz,3H),1.29-1.12(m,6H).

[0408] Example 40-0: (6-isopropyl-2-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-3-yl)boronic acid [ka] Compound 40-0 was prepared in the following manner. [ka] A mixture of allylpalladium chloride dimer (8.96 mg, 0.024 mmol), RockPhos (0.034 g, 0.073 mmol), and cesium carbonate (2.394 g, 7.35 mmol) was flushed with argon for several minutes, then anhydrous PhMe (5 mL) was added, followed by 2-((tetrahydro-2H-pyran-2-yl)oxy)ethan-1-ol (1.330 mL, 9.80 mmol). The reaction was heated to 90 °C for 3 minutes, then 2-bromo-6-isopropylpyridine (0.7 mL, 4.90 mmol) was added, and the reaction was continued at 90 °C for 30 minutes. The resulting mixture was filtered through a pad of CELITE, concentrated in vacuo, and purified by normal-phase chromatography (80 g column) using a running gradient of 0–15% EtOAc / heptane to give 1.018 g of compound 40-1 as an oil. 1 H NMR(500MHz,DMSO-d6)δ 7.60(dd,J=8.2,7.3Hz,1H),6.83(dt,J=7.3,0.6Hz,1H),6.61(dd,J=8.2,0.8Hz,1H),4.64(t,J=3.7Hz,1H),4.50-4.31(m,2H),3.93(ddd,J=1 1.3,6.0,3.8Hz,1H),3.83-3.66(m,2H),3.49-3.38(m,1H),2.91(h,J=6 .9Hz,1H),1.78-1.55(m,2H),1.56-1.38(m,4H),1.21(d,J=6.8Hz,6H).

[0409] [ka] A solution of 2-isopropyl-6-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine Compound 40-1 (1018 mg, 3.84 mmol), TMEDA (0.64 mL, 4.24 mmol), and anhydrous EtO (8 mL) was placed under a N atmosphere and cooled to -78 °C. n-BuLi (3.2 mL, 5.12 mmol) (1.6 M in hexanes) was then added dropwise over several minutes. The reaction turned orange and was allowed to warm to room temperature over 30 minutes, where it slowly turned red-orange. The reaction was re-cooled to -78 °C and B(O i Pr)3 (2.7 mL, 11.63 mmol) was added dropwise over several minutes. The reaction was allowed to warm to room temperature over 1 h. The reaction was quenched with 6 M HCl and then acidified to approximately pH 4 with 1 M HCl. The resulting biphasic mixture was stirred vigorously at room temperature for 30 min, then extracted with EtOAc. The combined organic layers were dried over Na2SO4, concentrated in vacuo, and purified by normal phase chromatography (120 g column) using a running gradient of 0–35% (3:1 EtOAc:EtOH) / heptane to afford 2.245 g of compound 40 as a clear gum.

[0410] Example 41-0: 2-(4-(1,2-difluoroethyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 41-0 was prepared in the following manner. [ka] To a solution of K2CO3 (6.62 g, 47.94 mmol) in THF / water (50 mL, 4:1) was added 1-bromo-4-iodo-2-methoxybenzene (5.0 g, 15.98 mmol) and potassium vinyltrifluoroborate (3.21 g, 23.97 mmol). The reaction was degassed with argon for 10 min. Next, Pd(dppf)Cl2-DCM complex (652 mg, 0.80 mmol) was added, and the reaction mixture was heated at 70 °C for 6 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 5–10% EtOAc / n-hexane to give 1.9 g of compound 41-1 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.48(d,J=8.1Hz,1H),6.93-6.83(m,1H),6.66(dd,J=17.6,10.9Hz,1H),5.75(d,J=17.6Hz,1H),5.29(d,J=10.9Hz,1H),3.90(d,J=15.4Hz,3H).

[0411] [ka] To a solution of compound 41-1 in THF was added HO (30 mL, 9:1), NMO (3.13 g, 26.73 mmol), and OsO (22 mg, 0.089 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and HO and separated. The organic layer was dried over NaSO and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 80–100% EtOAc / n-hexane to give 1.3 g of compound 41-2 as a solid. 1H NMR(300MHz,CDCl3)δ 7.51(d,J=8.1Hz,1H),6.97(d,J=1.9Hz,1H),6.82(ddd,J=8.1,1.9,0.7Hz,1H),4.81(dt,J=7.9,3.5Hz,1H),3.91(s,3H),3.7 8(ddd,J=10.9,7.1,3.6Hz,1H),3.64(ddd,J=11.3,8.1,4.9Hz,1H),2.60(dd,J=3.4,0.6Hz,1H),2.01(dd,J=7.1,4.9Hz,1H).

[0412] [ka] To a solution of compound 41-2 in THF (20 mL) was added DAST (3.5 mL, 26.31 mmol) dropwise at −78° C. The reaction mixture was stirred at room temperature for 16 h, then quenched with ice and extracted with EtOAc. The organic layer was dried over NaSO and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 0–10% EtOAc / n-hexane to give 150 mg of compound 41-3 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.56(dd,J=8.1,1.0Hz,1H),6.91(d,J=1.9Hz,1H),6.80(ddt,J=8.1,1.8,0.9Hz,1H),5.82-5.50(m,1H),4.91-4.21(m,2H),3.92(s,3H).

[0413] [ka] To a solution of KOAc (177 mg, 1.80 mmol) in DMSO (3 mL) was added compound 41-3 and B2Pin2 (303 mg, 1.19 mmol). The reaction mixture was degassed with argon for 10 minutes. Then, PdCl2(dppf)-DCM complex (24 mg, 0.03 mmol) was added, and the reaction mixture was heated at 100 °C for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 150 mg of compound 41. The crude compound was carried on directly to the next step without further purification.

[0414] Example 42-0: 2-(4-(difluoromethyl)-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 42-0 was prepared in the following manner. [ka] To a solution of methyl 4-bromo-3-methoxybenzoate (2.0 g, 8.16 mmol) in THF (15 mL) at −40° C. was added LiAlH (309 mg, 8.16 mmol). The resulting mixture was stirred at −40° C. for 45 minutes. The reaction mixture was quenched with saturated NH Cl (20 mL) at 0° C. and extracted twice with EtOAc (100 mL). The combined organic layers were dried over Na SO and concentrated in vacuo to give 1.6 g of compound 42-1 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.50(dd,J=8.0,0.6Hz,1H),6.98-6.91(m,1H),6.84-6.76(m,1H),4.67(d,J=5.5Hz,2H),3.91(s,3H).

[0415] [ka] To a solution of compound 42-1 (800 mg, 3.03 mmol) in DCM (15 mL) at 0 °C, DMP (2.56 g, 6.06 mmol) and NaHCO (510 mg, 6.06 mmol) were added. The resulting solution was stirred at room temperature for 10 h. The reaction mixture was filtered through a CELITE pad and concentrated in vacuo. The crude compound was purified by normal phase chromatography using a running gradient of 10% EtOAc / n-hexane to give 600 mg of compound 42-2 as a solid. 1 H NMR(600MHz,CDCl3)δ 9.96(s,1H),7.75(d,J=7.9Hz,1H),7.41(d,J=1.8Hz,1H),7.34(dd,J=7.9,1.8Hz,1H),3.98(s,3H).

[0416] [ka] To a solution of compound 42-2 (500 mg, 2.32 mmol) in DCM (30 mL) was added DAST (1.53 mL, 11.62 mmol). The resulting solution was stirred at 40 °C for 24 h. Then, HO (50 mL) was added to the reaction mixture, which was extracted twice with DCM (50 mL). The combined organic layers were dried over NaSO and concentrated in vacuo to give 490 mg of compound 42-3 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.62(dt,J=8.0,1.0,1.0Hz,1H),7.03(d,J=1.7Hz,1H),6.99-6.93(m,1H),6.61(t,J=56.4Hz,1H),3.94(s,3H).

[0417] [ka] To a solution of compound 42-3 (1.0 equiv.) and B2Pin2 in dioxane / DMSO (10 vol.), KOAc (3.0 equiv.) and PdCl2(dppf)-DCM complex (10 mol%) were added. The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with water, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give compound 42. 1 H NMR(400MHz,CDCl3)δ 7.73-7.67(m,1H),7.06-6.99(m,1H),6.75-6.42(m,1H),6.61(t,J=56.4Hz,1H),3.84(s,2H),1.23(s,11H).

[0418] Example 43-0: 2-(4-isopropyl-2-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 43-0 was prepared in the following manner. [ka] To a solution of 1-bromo-4-iodo-2-methoxybenzene (1.0 equiv.) in dioxane / HO (4:1) was added KCO (3.0 equiv.), an arylboronic acid ester (1.5 equiv.), and PdCl(dppf)-DCM complex (5 mol%). The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of n-hexane to give 940 mg of compound 43-1 as a colorless liquid. 1 H NMR(600MHz,CDCl3)δ 7.47(d,J=8.2Hz,1H),6.98(d,J=2.1Hz,1H),6.94(d,J=2.1Hz,1H),5.40-5.05(m,2H),3.92(s,3H),2.14(s,3H).

[0419] [ka] A solution of compound 43-1 (940 mg, 4.14 mmol) and 10% Pd—C (94 mg) in EtOAc (30 mL) was stirred under H for 1 h. The reaction mixture was filtered through a pad of CELITE and concentrated in vacuo to give 920 mg of compound 43-2. 1 H NMR(300MHz,CDCl3)δ 7.47(d,J=8.2Hz,1H),6.98(d,J=2.0Hz,1H),6.76(d,J=2.0Hz,1H),3.92(s,3H),2.92-2.82(m,,1H),1.24(d,J=6.9Hz,6H).

[0420] [ka] A solution of compound 43-2 (1.0 equiv.), B2Pin2, KOAc (3.0 equiv.), and PdCl2(dppf)-DCM complex (10 mol%) in dioxane (30.0 mL) was heated at 80 °C for 16 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 10 / 90 EtOAc / n-hexane to give 1.3 g of compound 43 as a solid. 1 H NMR(600MHz,CDCl3)δ 7.60(d,J=7.5Hz,1H),6.81(dd,J=7.6,1.4Hz,1H),6.70(s,1H),3.82(s,3H),2.87(h,J=7.0Hz,1H),1.24(s,18H).

[0421] Example 44-0:2 2-(2-ethoxy-4-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 44-0 was prepared in the following manner. [ka] To a solution of 3-isopropylphenol (2.0 g, 14.68 mmol) in AcOH (16 mL) was added KIO (629 mg, 2.93 mmol). Then, iodine (1.5 g, 5.87 mmol) was added portionwise at room temperature. The resulting solution was stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and extracted twice with EtOAc (100 mL). The combined organic layers were washed with water, saturated NaHCO solution, and then brine. The combined organic layers were dried over NaSO, filtered, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of n-hexane to give 1.6 g of compound 44-1 as a brown liquid. 1 H NMR(300MHz,CDCl3)δ 7.54(d,J=8.2Hz,1H),6.89(d,J=2Hz,1H),6.58(dd,J=8.0,2.0,1Hz),2.84(m,1H),1.22(d,J=6.9Hz,6H).

[0422] [ka] To a solution of compound 44-1 (600 mg, 2.48 mmol) in EtOH (15 mL) was added KCO (1.03 g, 7.44 mmol) at room temperature. After 10 min, ethyl iodide (0.6 mL, 7.44 mmol) was added dropwise, and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with HO and extracted twice with EtOAc (50 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 0–10% EtOAc / n-hexane to give 550 mg of compound 44-2 as a colorless liquid. 1H NMR(600MHz,CDCl3)δ 7.65(d,J=8.0,1H),6.68(d,J=2.0Hz,1H),6.60(dd,J=8.0,2.0Hz,1H),4.09( q,J=6.9Hz,2H),2.85(m,1H),1.48(t,J=6.9Hz,3H),1.24(s,3H),1.23(s,3H).

[0423] [ka] A solution of compound 44-2 (1.0 equiv.), B2Pin2 in dioxane (10 vol.), KOAc (3.0 equiv.), and PdCl2(dppf)-DCM complex (10 mol%) was heated at 80 °C for 16 h. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with H2O, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 400 mg of compound 44-0 as a brown liquid. LC-MS = 291.30 [M+H] + , retention time = 1.97 min.

[0424] Example 45-0: 2-(2-methoxy-4-(tetrahydrofuran-3-yl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 45-0 was prepared in the following manner. [ka] To a solution of 1-bromo-4-iodo-2-methoxybenzene (1.5 g, 0.003 mmol) in THF (12 mL) at −20° C., i-PrMgCl-LiCl (5.3 mL, 0.012 mmol) was added dropwise and stirred for 30 min. A solution of dihydrofuran-3(2H)-one (0.824 g, 0.003 mmol) in THF (12 mL) was added dropwise. This was stirred at room temperature for 2 h. The reaction mixture was quenched with NH4Cl solution at 0° C., extracted with EtOAc, and the organic layer was concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 30:70 EtOAc:n-hexane to give 450 mg of compound 45-1 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.51(dd,J=8.2,1.8Hz,1H),7.12(s,1H),6.90(dd,J=8.0,2.0,Hz,1H),4.24-3.99(m,4H),3.92(s,3H),2.30-2.15(m,2H).

[0425] [ka] To a solution of compound 45-1 (0.540 g, 1.98 mmol) in DCM (10 mL) at −78 °C, BF₃·OEt₂ (1.40 g, 9.9 mmol) was added, followed by dropwise addition of Et₃SiH (1.38 mL, 11.9 mmol). The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was quenched with NH₄Cl solution and extracted with EtOAc. The organic layer was concentrated in vacuo to give 200 mg of a mixture of compound 45-2 and 3-(4-bromo-3-methoxyphenyl)-2,5-dihydrofuran. This mixture was subjected to a hydrogenation step using 20% ​​Pd / C (60 mg) in EtOAc (10 mL) for 12 h. The reaction mixture was filtered through a CELITE pad, and the organic layer was concentrated in vacuo to give 250 mg of compound 45-2 as a colorless liquid. 1H NMR(300MHz,CDCl3)δ 7.45(d,J=8.2Hz,1H),6.79(d,J=2.0Hz,1H),6.74(dt,J=8.1,1.3Hz,1H),4.16-4.01(m,2H),3.96-3.90(m,1H) ,3.90(s,3H),3.78-3.69(m,1H),3.43-3.30(m,1H),2.47-2.28(m,1H),2.05-1.90(m,1H).LC-MS=258.90[M+H] + , retention time = 1.56 min.

[0426] [ka] To a sealed tube containing aryl bromide compound 45-2 (1.0 equiv.) and B2Pin2 in dioxane (12 mL) was added KOAc (3.0 equiv.) and PdCl2(dppf)-DCM complex (10 mol%). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with H2O and extracted twice with EtOAc. The combined organic layers were washed with H2O, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give 310 mg of compound 45 as a crude material. LC-MS = 305.05 [M+H] + , retention time = 1.57 min.

[0427] Example 46-0: 2-(2-methoxy-4-(1-methoxycyclopropyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 46-0 was prepared in the following manner. [ka] To a solution of methyl 4-bromo-3-methoxybenzoate (4.0 g, 16.32 mmol) in THF (80 mL) at −78 °C, Ti(iPrO) (4.6 g, 16.32 mmol) was added dropwise, and the resulting solution was stirred at −78 °C for 10 min. Next, ethylmagnesium bromide (21.76 mL, 65.28 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with saturated NH Cl and extracted twice with EtOAc (200 mL). The combined organic layers were washed with water, brine, then dried over Na SO , filtered, and evaporated in vacuo. Crude compound 46-1 was used directly in the next step.

[0428] [ka] To a solution of compound 46-1 (1.0 g, 4.11 mmol) in dioxane (10 mL) was added TBAB (1.32 g, 4.11 mmol), KOH (920 mg, 16.44 mmol), and MeI (0.76 mL, 12.23 mmol) at room temperature. The resulting mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, HO was added, and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine, dried over NaSO, filtered, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 2–3% EtOAc / n-hexane to give 1.2 g of compound 46-2 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.47-7.42(m,1H),6.97(d,J=2.0Hz,1H),6.68(dd,J=8.2,2.0Hz,1H),3.91(s ,3H),3.22(s,3H),1.23-1.14(m,2H),0.99-0.90(m,2H);LC-MS=256.75[M+H] + , retention time = 1.60 min.

[0429] [ka] To a solution of compound 46-2 (500 mg, 1.95 mmol) and B2Pin2 (545.5 mg, 2.15 mmol) in dioxane (5 mL) was added KOAc (575 mg, 5.6 mmol) and PdCl2(dppf)-DCM complex (220 mg, 0.273 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with water, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the crude material, which was purified by normal-phase chromatography using a running gradient of 5–8% EtOAc / n-hexane to give compound 46 as a colorless liquid.

[0430] Example 47-0: 2-(2-methoxy-4-(1-methoxycyclobutyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 47-0 was prepared in the following manner. [ka] A solution of 1-bromo-4-iodo-2-methoxybenzene (2.0 g, 6.39 mmol) and cyclobutanone (1.34 g, 19.17 mmol) in THF (20 mL) under a N atmosphere was cooled to −78 °C. Next, n-BuLi in n-hexane (2.8 mL, 2.5 M, 7.02 mmol) was added over 10 min, and the resulting mixture was stirred at −78 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (50 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were washed with HO (50 mL), brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 10–30% EtOAc / n-hexane to give 500 mg of compound 47-1 as a colorless viscous liquid. 1H NMR(400MHz,CDCl3)δ 7.51(d,J=8.2Hz,1H),7.07(d,J=2.0Hz,1H),6.96(dd,J=8.1,2.0Hz,1H),3.92(s ,3H),2.59-2.47(m,2H),2.42-2.30(m,2H),2.09-1.97(m,2H),1.77-1.64(m,1H).

[0431] [ka] To a suspension of NaH (47 mg, 1.16 mmol) in DMF (1 mL) at 0 °C was added compound 47-1 (250 mg, 0.97 mmol) in DMF (1 mL) under a N atmosphere. The reaction was stirred at room temperature for 10 min. Next, MeI (206 mg, 1.45 mmol) was added at 0 °C, and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were washed with HO (50 mL), brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 10–30% EtOAc / n-hexane to give 220 mg of compound 47-2 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 7.51(d,J=8.2Hz,1H),6.96(d,J=2.0Hz,1H),6.90(dd,J=8.1,2.0Hz,1H),3.91 (s,3H),2.94(s,3H),2.40-2.30(m,4H),2.00-1.87(m,1H),1.75-1.62(m,1H).

[0432] [ka] To a solution of compound 47-2 (200 mg, 0.74 mmol) and B2Pin2 (225 mg, 0.88 mmol) in dioxane (3 mL) was added KOAc (218 mg, 2.22 mmol) and PdCl2(dppf)-DCM complex (30 mg, 0.04 mmol). The reaction mixture was heated at 80 °C for 16 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with water, then brine, dried over Na2SO4, filtered, and concentrated in vacuo to give compound 47. 1 H NMR(300MHz,CDCl3)δ 7.67(d,J=7.5Hz,1H),7.06-6.96(m,2H),3.85(s,3H),2.93(s,3H),2.40-2.30(m,4H),2.00-1.87(m,1H),1.75-1.62(m,1H),1.35(s,12H).

[0433] Example 48-0: 2-(2-(2-fluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 48-0 was prepared in the following manner. [ka] To a solution of 2-bromophenol (1.6 g, 9.248 mmol) and K2CO3 (3.82 g, 27.74 mmol) in DMF (10 mL), 1-fluoro-2-iodoethane (1.93 g, 11.098 mmol) was added and stirred at 70 °C for 3 h. The reaction mixture was quenched with HO and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 0–10% EtOAc / n-hexane to give 1.0 g of compound 48-1 as a colorless liquid.

[0434] [ka] Argon was bubbled through dioxane (10.0 mL) for 15 minutes, followed by the addition of compound 48-1 (1.0 g, 4.56 mmol), B2Pin2 (2.31 g, 9.129 mmol), KOAc (1.34 g, 13.69 mmol), and PdCl2(dppf)-DCM complex (372.38 g, 0.456 mmol). Argon was bubbled through the reaction mixture for an additional 10 minutes, and the reaction was then heated at 100 °C for 4 hours. The reaction mixture was diluted with MTBE and filtered through a pad of CELITE. The filtrate was dried over Na2SO4 and concentrated in vacuo to give 560 mg of compound 48 as a solid. The crude compound was used in the next reaction without further purification. 1 H NMR(300MHz,CDCl3)δ 7.63(dd,J=7.3,1.9Hz,1H),7.45-7.30(m,1H),7.06-6.93(m,1H),6.85(dd,J=8.3,0.8Hz,1H),4.88-4.78 (m,1H),4.67(ddd,J=4.4,3.7,1.0Hz,1H),4.29-4.22(m,1H),4.21-4.10(m,1H),1.35(s,6H),1.26(s,6H).

[0435] Example 49-0: 2-(2-(2,2-difluoroethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 49-0 was prepared in the following manner. [ka] To 2-bromophenol (1 g, 5.78 mmol) in DMF (10 mL) was added K2CO3 (1.59 g, 11.5 mmol), KI (1.59 g, 9.57 mmol), and 2-bromo-1,1-difluoroethane (1.67 g, 11.5 mmol). The reaction mixture was heated at 70 °C for 3 h. The reaction mixture was quenched with HO and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, and the filtrate was concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 1% EtOAc / n-hexane to give 0.955 g of compound 49-1 as an oil. 1 H NMR(300MHz,CDCl3)δ 7.65-7.51(m,1H),7.35-7.20(m,1H),6.97-6.83(m,2H),6.16(tt,J=55.1,4.2Hz,1H),4.24(td,J=12.9,4.2Hz,2H).

[0436] [ka] A stirred suspension of compound 49-1 (0.9 g, 3.79 mmol) in dioxane (15 mL) was purged with argon, followed by the addition of KOAc (0.745 g, 7.59 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.44 g, 5.68 mmol), and PdCl(dppf)-DCM complex (0.154 g, 0.189 mmol). The reaction was purged for an additional 15 min and then heated at 100 °C for 3 h. The reaction mixture was filtered through a pad of CELITE and washed with EtOAc (20 mL). The organic layer was washed with HO and brine, dried over NaSO, and concentrated in vacuo to give 1.1 g of compound 49 as a solid. 1H NMR(300MHz,CDCl3)δ 7.67(dd,J=7.3,1.8Hz,1H),7.40(ddd,J=8.3,7.4,1.9Hz,1H),7.03(td,J=7.3,0.9Hz,1H ),6.85(d,J=8.3Hz,1H),6.41-5.81(m,1H),4.35-4.05(m,2H),1.35(s,6H),1.26(s,6H).

[0437] Example 50-0: 2-(2-(2,3-difluoropropoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [ka] Compound 50-0 was prepared in the following manner. [ka] To a solution of 2-bromophenol (2 g, 11.56 mmol), K2CO3 (4.8 g, 34.68 mmol), and KI (574 mg, 3.46 mmol) in acetone (30 mL) was added allyl bromide (1.54 g, 12.70 mmol). The reaction was heated at 60 °C for 3 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 0–10% EtOAc / n-hexane to give 2.4 g of compound 50-1 as a colorless liquid. 1 H NMR (600 MHz, chloroform-d) δ 7.59-7.49 (m, 1H), 7.31-7.16 (m, 1H), 6.90 (d, J = 8.3 Hz, 1H), 6.84 (t, J = 7.6, 1H), 6.15-5.97 (m, 1H), 5.49 (dt, J = 16.9, 1.9 Hz, 1H), 5.31 (m 1H), 4.62 (dd, J = 4.9, 1.9 Hz, 2H).

[0438] [ka] To a solution of compound 50-1 (2.4 g, 11.26 mmol) in THF was added HO (35 mL, 9:1), NMO (4.0 g, 33.78 mmol), and OsO (29 mg, 0.11 mmol) at 0 °C. The reaction was stirred at room temperature for 16 h. The reaction mixture was partitioned between EtOAc and water. The organic layer was dried over NaSO and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 80–100% EtOAc / n-hexane to give 2.5 g of compound 50-2 as a solid. 1 H NMR(600MHz,CDCl3)δ 7.54(dd,J=7.9,1.7Hz,1H),7.30-7.23(m,1H),6.94-6.85(m,2H),4.19-4. 08(m,3H),3.92-3.81(m,2H),2.87(d,J=5.1Hz,1H),2.26(t,J=6.1Hz,1H).

[0439] [ka] To a solution of compound 50-2 (2.8 g, 11.33 mmol) in THF (40 mL) was added DAST (6 mL, 1.22 mmol) dropwise at −78° C. The reaction was then stirred at room temperature for 16 h. The reaction mixture was quenched with ice and extracted with EtOAc. The organic layer was dried over NaSO and concentrated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 0–10% EtOAc / n-hexane to give 1.3 g of compound 50-3 as a colorless liquid. 1 H NMR(600MHz,CDCl3)δ 7.55(dd,J=7.8,1.6Hz,1H),7.36-7.15(m,1H),7.05-6.70(m,2H),5.24-4.92(m,1H),4.90-4.72(m,2H),4.39-4.22(m,2H).

[0440] [ka] To a solution of KOAc (468 mg, 4.77 mmol) in DMSO (6 mL) was added compound 50-3 (400 mg, 1.59 mmol) and B2Pin2 (809 mg, 3.18 mmol). The reaction was degassed with argon gas for 10 minutes. PdCl2(dppf)-DCM complex (65 mg, 0.08 mmol) was then added, and the resulting mixture was heated at 80 °C for 2 hours. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo to give 350 mg of compound 50. The crude compound was carried on directly to the next step without further purification.

[0441] Example 51-0: (4-chloro-5-isopropyl-2-methoxyphenyl)boronic acid [ka] Compound 51-0 was prepared in the following manner. [ka] To a solution of 4-bromo-3-chlorophenol (3 g, 1.05 mmol) in DMF (30 mL) was added K2CO3 (4 g, 28.98 mmol) at 0 °C. After 10 min, methyl iodide (3.06 g, 21.73 mmol) was added dropwise, and the reaction mixture was stirred at room temperature for 7 h. The reaction mixture was then diluted with HO and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo to give 2.1 g of compound 51-1 as a light brown liquid. 1 H NMR(600MHz,CDCl3)δ 7.47(d,J=8.9Hz,1H),7.01(d,J=3.0Hz,1H),6.70(dd,J=8.8,3.0Hz,1H),3.79(s,3H).

[0442] [ka] To a solution of compound 51-1 (1.0 equiv.) in dioxane / HO (4:1) was added KCO (3.0 equiv.), allylboronic acid ester (1.5 equiv.), and PdCl(dppf)-DCM complex (5 mol%). The reaction mixture was heated at 100 °C for 6 h. The reaction mixture was diluted with HO and extracted twice with EtOAc. The combined organic layers were washed with HO, then brine, dried over NaSO, filtered, and concentrated in vacuo. The crude material was purified by normal-phase chromatography using a running gradient of 5 / 95 EtOAc / n-hexane to give 1.6 g of compound 51-2 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 7.26(s,1H),7.12(d,J=8.5Hz,1H),6.91(d,J=2.6Hz,1H),5.22-5.17(m,1 H),4.94(dq,J=1.9,0.9Hz,1H),3.79(s,3H),2.08(dd,J=1.6,0.9Hz,3H).

[0443] [ka] A solution of compound 51-2 (1.8 g, 9.85 mmol) and 10% Pd—C (100 mg) in EtOAc (30 mL) was stirred under H for 7 h. The reaction mixture was filtered through a pad of CELITE and concentrated in vacuo to give 1.6 g of compound 51-3. 1 H NMR(300MHz,CDCl3)δ 7.26(s,1H),7.19(d,J=8.6Hz,1H),6.90(d,J=2.7Hz,1H),3.78-3.77(m,3H),3.33(m,1H),1.23(d,J=0.6Hz,3H),1.20(d,J=0.7Hz,3H).

[0444] [ka] To a solution of compound 51-3 (1.6 g, 8.66 mmol) in chloroform (70 mL) was added AgSO (3.24 g, 13.05 mmol) at room temperature. Then, iodine (2.64 g, 13.03 mmol) was added portionwise at room temperature. The resulting solution was stirred at room temperature for 12 h. The reaction mixture was filtered through a CELITE pad. The filtrate was extracted twice with EtOAc (100 mL), and the combined organic layers were washed with HO and brine, dried over NaSO, filtered, and evaporated in vacuo. The crude compound was purified by normal-phase chromatography using a running gradient of 10 / 90 EtOAc / n-hexane to give 1.03 g of compound 51-4 as a pale yellow liquid. 1 H NMR(300MHz,CDCl3)δ 7.62(s,1H),6.79(s,1H),3.85(s,3H),3.26(m,1H),1.22(d,J=7.6Hz,3H),1.19(d,J=7.6Hz,3H).

[0445] [ka] To a solution of compound 51-4 (1.03 g, 3.34 mmol) in dry THF (15 mL) at −78 °C, n-BuLi (1.67 mL, 2.5 M in hexane, 3.34 mmol) was added dropwise. Then, B( i PrO) (0.93 mL, 8.35 mmol) was added dropwise at −78° C., and the mixture was allowed to warm to room temperature slowly and stirred for 3 h. The reaction mixture was quenched with HO and extracted twice with EtOAc (50 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 350 mg of compound 51 as a solid. 1 H NMR(300MHz,CDCl3)δ 7.74(s,1H),6.90(s,1H),3.89(s,3H),3.39-3.26(m,1H),1.23-1.19(m,6H).

[0446] Example 52-0: 6-Isopropyl-2-(2-methoxyethoxy)pyridin-3-yl)boronic acid [ka] Compound 52-0 was prepared in the following manner. [ka] A mixture of allylpalladium chloride dimer (9.09 mg, 0.025 mmol), RockPhos (34.9 mg, 0.075 mmol), and cesium carbonate (2428 mg, 7.45 mmol) was flushed with argon for several minutes, then anhydrous PhMe (5 mL) was added, followed by 2-methoxyethanol (0.8 mL, 10.15 mmol). The reaction was heated to 90 °C for 3 minutes, then 2-bromo-6-isopropylpyridine (0.71 mL, 4.97 mmol) was added, and the reaction was continued at 90 °C for 1 hour. The resulting reaction was filtered through a pad of CELITE and concentrated in vacuo. The crude material was purified by normal-phase chromatography (40 g) using a running gradient of 0–25% EtOAc / heptane to give 848 mg of compound 52-1 as an oil.

[0447] [ka] A solution of compound 52-1 (848 mg, 4.34 mmol) and TMEDA (0.8 mL, 5.30 mmol) in anhydrous EtO (9 mL) was placed under a N atmosphere and cooled to -78 °C. n-BuLi (4 mL, 6.40 mmol) (1.6 M in hexanes) was then added dropwise over several minutes. The reaction turned orange and was allowed to warm to room temperature over 30 minutes, where it slowly turned red-orange. The reaction was re-cooled to -78 °C and B(O iPr)3 (3 mL, 12.92 mmol) was added dropwise over several minutes. The reaction was allowed to warm to room temperature over 30 minutes. The reaction was quenched with 6 M HCl and then acidified to approximately pH 4 with 1 M HCl. The resulting biphasic mixture was stirred vigorously at room temperature for 30 minutes, then extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography (80 g column) using a running gradient of 0–25% (3:1 EtOAc / EtOH) / heptane to afford 813 mg of compound 52 as a yellow gum. 1 H NMR(500MHz,DMSO-d6)δ 7.88(d,J=7.3Hz,1H),7.69(s,2H),6.87(d,J=7.2Hz,1H),4.48-4.41(m,2H),3.68(ddd,J=6.4, 4.2,1.5Hz,2H),3.31(s,3H),2.95-2.87(m,1H),1.21(dd,J=6.9,2.1Hz,6H).LC-MS=240.3[M+H] + .

[0448] The following compounds were prepared by the same route used for compound 4-0.

[0449] [Table 46]

[0450] [Table 47]

[0451] [Table 48]

[0452] [Table 49]

[0453] [Table 50]

[0454] [Table 51]

[0455] Compound 53-0: tert-butyl 4-amino-1-thia-8-azaspiro[4.5]decane-8-carboxylate 1,1-dioxide [ka] Compound 53-0 was prepared in the following manner. [ka] To a suspension of dihydrothiophen-2(3H)-one (0.123 g, 1.20 mmol) in THF (3 mL) was added LiHMDS (1.2 mL, 1.23 mmol) at -78 °C and stirred for 1 h. Next, tert-butyl 4-oxopiperidine-1-carboxylate (0.200 g, 1.0 mmol) in THF (3 mL) was added to the reaction mixture at -78 °C and stirred at the same temperature for 2 h. The reaction mixture was quenched with saturated NH4Cl solution and extracted with EtOAc (20 mL). The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 30–40% EtOAc / n-hexane to give 0.155 g of compound 53-1 as a solid. 1 H NMR(300MHz,CDCl3)δ 3.92(br s,2H),3.75-3.59(m,1H),3.32-3.21(m,2H),3.13(s,2H),2.65(s,9H).LC-MS=202.10[M+H] + (De-Boc), retention time = 1.48 minutes.

[0456] [ka] To a suspension of compound 53-1 (0.150 g, 0.497 mmol) in DCM (5 mL) was added EtN (0.69 mL, 4.97 mmol) and MsCl (0.077 mL, 0.995 mmol) at 0 °C. The reaction was allowed to reach room temperature and stirred for 18 h. The reaction mixture was quenched with saturated NaHCO solution and extracted with DCM (10 mL). The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 30–40% EtOAc / n-hexane to give 0.080 g of compound 53-2 as a colorless liquid. 1 H NMR(300MHz,CDCl3)δ 3.54(t,J=5.9Hz,2H),3.44(t,J=5.9Hz,2H),3.29-3.22(m,2H),3.05-2.94(m,4H),2.34(t,J=6.0Hz,2H),1.47(s,9H).LC-MS=284.05[M+H] + , retention time = 1.64 min.

[0457] [ka] To a suspension of compound 53-2 (0.3 g, 1.06 mmol) in MeOH (3 mL) was added EtN (0.297 mL, 2.12 mmol). The reaction mixture was heated at 70 °C for 32 h. The reaction was concentrated in vacuo. The crude product was purified by normal phase chromatography using a running gradient of 5-10% EtOAc / n-hexane to give 0.56 g of compound 53-3 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 4.13(s,2H),3.73(s,3H),3.05-2.94(m,2H),2.94-2.84(m,2H),2.77(dd,J=10.8,6. 2Hz,1H),2.52-2.31(m,2H),2.21-2.09(m,1H),1.68(t,J=12.9Hz,2H),1.46(s,10H).

[0458] [ka] To a suspension of compound 53-3 (0.050 g, 0.158 mmol) in DCM (3 mL) was added mCPBA (0.070 g, 0.317 mmol) portionwise at 0 °C, and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO and NaSO and extracted twice with DCM (10 mL). The organic layer was washed with brine, dried over NaSO, and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 50–70% EtOAc / n-hexane to give 0.034 g of compound 53-4 as a colorless liquid. 1 H NMR(400MHz,CDCl3)δ 3.94(s,2H),3.76(s,3H),3.43(s,1H),3.35(ddd,J=13.4,9.4,4.0Hz,1H),3.23(s,1H),3.09(dt,J=13.4,9.0Hz,1H),2.99(dd,J =11.1,6.3Hz,1H),2.45(ddt,J=14.0,11.2,9.3Hz,1H),2.24(dddd,J=14.0,8.8,6.3,4.0Hz,2H),2.15-2.02(m,3H),1.45(s,9H).

[0459] [ka] To a suspension of compound 53-4 (0.56 g, 1.61 mmol) in THF:HO (6 mL, 1:1), LiOH·HO (0.135 g, 3.22 mmol) was added at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The reaction mixture was acidified with saturated citric acid to pH = 4 and extracted twice with DCM (20 mL). The combined organic layers were washed with brine, dried over NaSO, and concentrated in vacuo to give 0.4 g of compound 53-5 as a solid. 1H NMR(300MHz,DMSO-d6)δ 3.79(d,J=13.2Hz,2H),3.52-3.34(m,2H),3.25-3.08(m,2H),2.94(dd,J=10.4,7.1Hz,1H ),2.22-2.16(m,1H),2.10-1.95(m,4H),1.57(ddd,J=15.0,11.2,4.9Hz,1H),1.39(s,9H).

[0460] [ka] To a solution of compound 53-5 (0.5 g, 1.49 mmol) in PhMe (30 mL) and EtN (0.313 mL, 2.24 mmol), diphenylphosphoryl azide (0.619 g, 2.24 mmol) was added dropwise at room temperature. The reaction was then heated at 110 °C for 1.5 h. The reaction was cooled to room temperature, and BnOH (0.486 g, 4.49 mmol) was added dropwise and stirred at 100 °C for 10 h. The reaction mixture was quenched with saturated NaCO and extracted with EtOAc. The combined organic layers were dried over NaSO and concentrated in vacuo. The crude product was purified by normal-phase chromatography using a running gradient of 40–70% EtOAc / n-hexane to give 0.350 g of compound 53-6 as a solid. 1 H NMR(400MHz,CDCl3)δ 7.42-7.29(m,5H),5.11(ABq,J=12.0Hz,2H),3.71(brs,1H),3.56(brs,2H),3.26-3.10(m,2H ),2.18-2.06(m,2H),1.98-1.87(m,2H),1.80-1.75(m,2H),1.68-1.64(m,2H),1.45(s,9H)).

[0461] [ka] To a solution of compound 53-6 (350 mg, 0.79 mmol) in THF (30.0 mL) was added 10% Pd—C (70 mg) under H. The reaction was stirred for 10 h. The reaction mixture was filtered through a CELITE pad and concentrated in vacuo to give 250 mg of compound 53-7. LC-MS=249 M-tBu+H. + , retention time = 1.27 min.

[0462] [ka] To a solution of compound 53-7 in dioxane, 4M HCl in dioxane was added dropwise at 0° C. for 5 minutes. Then, it was stirred at room temperature for 2 hours. The reaction was concentrated in vacuo to give 30 mg of compound 53. LC-MS=205.10 [M+H] + , retention time = 0.10 min.

[0463] Compound 54-0: tert-butyl (4-(methoxymethyl)piperidin-4-yl)carbamate [ka] Compound 54-0 was prepared in the following manner. [ka] To a solution of ethyl piperidine-4-carboxylate (10.0 g, 63.61 mmol) in DCM (100 mL) was added TEA (19.3 g, 190.84 mmol) at 0 °C. After 15 min, benzoyl chloride (9.84 g, 69.97 mmol) was added dropwise at 0 °C. The reaction was then allowed to reach room temperature over 16 h. The reaction mixture was quenched with ice-cold HO and extracted with DCM. The combined organic layers were washed with 2 N HCl followed by brine, dried over NaSO, and concentrated in vacuo to give 13.0 g of compound 54-1 as a solid. 1H NMR(300MHz,CDCl3)δ 7.46-7.33(m,5H),4.53(s,1H),4.15(q,J=7.1Hz,2H),3.75(s,1H),3.04(s,2H),2.57 (tt,J=10.7,4.0Hz,1H),2.12-1.55(m,4H),1.26(t,J=7.1Hz,3H).LC-MS=262.1[M+H] + , retention time = 0.83 min.

[0464] [ka] To a solution of diisopropylamine (2.50 g, 24.491 mmol) in THF (20 mL) at −78° C., n-BuLi (2.5 M in n-hexane, 9.20 mL, 22.960 mmol) was added dropwise, and the reaction was allowed to reach 0° C. for 10 minutes. The reaction was then cooled to −78° C., and compound 54-1 (4 g, 15.307 mmol) in THF (10 mL) was added dropwise. After 1 hour at −78° C., bromo(methoxy)methane (2.50 g, 19.899 mmol) was added dropwise at −78° C., and the reaction was allowed to reach room temperature over 16 hours. The reaction mixture was quenched with saturated NH4Cl in HO, extracted with EtOAc, and the combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using a running gradient of 30-40% EtOAc / n-hexane to give 3.50 g of compound 54-2 as a colorless sticky mass. 1 H NMR(300MHz,CDCl3)δ 7.46-7.33(m,5H),4.53(s,1H),4.15(q,J=7.1Hz,2H),3.75(s,1H),3.04(s,2H),2.57 (tt,J=10.7,4.0Hz,1H),2.12-1.55(m,4H),1.26(t,J=7.1Hz,3H).LC-MS=306.05[M+H] + , retention time = 1.49 min.

[0465] [ka] To a solution of compound 54-2 (3.50 g, 11.462 mmol) in EtOH (35 mL) was added NaOH (687 mg, 17.192 mmol) in HO (2.8 mL) at room temperature and stirred at 50 °C for 8 hours, then at room temperature for 48 hours. The reaction mixture was acidified with KHSO and extracted with EtOAc. The combined organic layers were washed with brine solution, dried over NaSO, and concentrated in vacuo to give 3.0 g of compound 54-3 as a white sticky mass. LC-MS = 278.15 [M+H] + , retention time = 1.37 min.

[0466] [ka] To a solution of compound 54-3 (1.0 g, 3.61 mmol) and EtN (1.09 g, 10.830 mmol) in PhMe (10 mL) was added diphenylphosphoryl azide (1.19 g, 4.332 mmol) dropwise at room temperature. The reaction was stirred at reflux for 3 h. The reaction mixture was diluted with EtOAc, washed with water, followed by saturated NaCO solution and brine, dried over NaSO, and concentrated in vacuo. The resulting residue was taken up in THF (10 mL) and KO t Bu (810 mg, 7.220 mmol) was added at room temperature. The reaction was stirred at room temperature for 20 minutes. The reaction mixture was quenched with saturated NH4Cl and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The crude material was purified by normal phase chromatography using a running gradient of 30-40% EtOAc / n-hexane to give 600 mg of compound 54-4 as a colorless sticky product. LC-MS=349.15 [M+H] + , retention time = 1.50 min.

[0467] [ka] To a solution of compound 54-4 (350 mg, 1.004 mmol) in EtOH (4.5 mL) was added NaOH (241 mg, 6.026 mmol) in HO (1 mL) at room temperature and stirred at 90 °C for 16 hours. The reaction mixture was concentrated in vacuo. The resulting residue was diluted with EtOAc, washed with water, dried over NaSO, and concentrated in vacuo to give 250 mg of compound 54 as a colorless sticky product. LC-MS = 245.20 [M+H] + , retention time = 1.23 min.

[0468] Compound 55-0: tert-butyl (3-(2-hydroxypropan-2-yl)pyrrolidin-3-yl)carbamate [ka] Compound 55-0 was prepared in the following manner. [ka] To a solution of methyl (tert-butoxycarbonyl)serinate (10.00 g, 45.639 mmol) in DCM (100 mL), pyridine (4.43 mL, 57.222 mmol) and Cbz-Cl (50% in PhMe, 14.22 mL, 50.203 mmol) were slowly added over 30 min at −50° C. The reaction was then stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (100 mL) and 20% citric acid solution (500 mL). The aqueous layer was extracted twice with DCM (500 mL). The combined organic layers were washed with 5% NaHCO solution and brine (200 mL), dried over NaSO, and concentrated in vacuo. The product was purified by normal-phase chromatography using a running gradient of 20% EtOAc / n-hexane to give 12.50 g of compound 55-1 as a solid. 1H NMR(400MHz,CDCl3)δ 7.38(d,J=5.1Hz,5H),5.38-5.25(m,1H),5.15(s,2H),4.63-4.48(m,2H),4 .41(dd,J=10.8,3.4Hz,1H),3.74(s,3H),1.44(s,9H).LC-MS=254.1[M-100] + (De-Boc), retention time = 1.31 minutes.

[0469] [ka] To a solution of compound 55-1 (6.00 g, 16.989 mmol) in N,N-dimethylformamide (60 mL) was added K2CO3 (4.695 g, 33.979 mmol) slowly over 5 min at room temperature. The reaction was then sealed and stirred at 65 °C for 3 h. The reaction mixture was diluted with HO (500 mL) and extracted twice with EtOAc (100 mL). The combined organic layers were washed with brine solution (300 mL), dried over Na2SO4, and concentrated in vacuo. The product was purified by normal-phase chromatography using a running gradient of 10% EtOAc / hexane to give 3.00 g of compound 55-2 as a colorless liquid. 1 H NMR(400MHz,DMSO-d6)δ 8.34(s,1H),7.46-7.32(m,1H),5.65(s,1H),5.49(s,1H),3.72(s,3H),1.41(s,9H).LC-MS=102.1[M-100] + (De-Boc), retention time = 1.28 minutes.

[0470] [ka] To a solution of compound 55-2 (3.7 g, 18.398 mmol) in DCM (30 mL) and TFA (0.1 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (4.36 g, 18.398 mmol) slowly over 5 min at 0 °C. The reaction was stirred at room temperature for 16 h. The reaction mixture was diluted with HO (50 mL) and extracted twice with DCM (50 mL). The combined organic layers were washed with aqueous NaHCO and brine (50 mL), and the organic layer was dried over NaSO and concentrated in vacuo. The product was purified by normal-phase chromatography using a running gradient of 20% EtOAc / n-hexane to give 1.90 g of compound 55-3 as a yellow liquid. 1 H NMR(400MHz,CDCl3)δ 7.39-7.27(m,5H),3.73(s,3H),3.64(q,J=13.0Hz,2H),2.88(s,1H),2.81(d,J=10.3Hz, 1H),2.67-2.52(m,2H),2.08-1.93(m,1H),1.58(s,1H),1.42(s,9H).LC-MS=335.2[M+H] + , retention time = 1.04 min.

[0471] [ka] To a solution of compound 55-3 (1.9 g, 5.685 mmol) in anhydrous THF (25 mL) was slowly added a solution of 3 M MeMgBr in EtO (9.475 mL, 28.426 mmol) over 5 min at 0 °C. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated NHCl solution (20 mL), diluted with HO (60 mL), and extracted twice with EtOAc (30 mL). The combined organic layers were washed with brine (20 mL), dried over NaSO, and concentrated in vacuo. The product was purified by normal-phase chromatography using a running gradient of 1–2% MeOH / DCM to give 900 mg of compound 55-4 as a yellow liquid. 1H NMR(400MHz,CDCl3)δ 7.39-7.12(m,5H),4.85(s,1H),3.67-3.51(m,2H),2.90(d,J=10.6Hz,1H),2.77-2.58(m,2H),2.55(d,J=10 .1Hz,1H),2.34-2.18(m,1H),1.91-1.78(m,1H),1.40(s,9H),1.18(s,3H),1.16(s,3H).LC-MS=335.1[M+H] + , retention time = 1.08 min.

[0472] [ka] To a solution of compound 55-4 (900 g, 2.692 mmol) in MeOH (20 mL), 10% Pd / C, 50% water (1.432 g, 13.463 mmol) was slowly added at 30 °C. The reaction was stirred at room temperature under H (60 psi) for 1 h. The reaction mixture was filtered through a CELITE pad. The filtrate was concentrated in vacuo to give 640 mg of compound 55 as a yellow liquid. 1 H NMR(400MHz,DMSO-d6)δ 4.92(s,1H),3.31(s,2H),2.99-2.77(m,3H),2.72-2.62(m,1H),2.02-1.80(m,2H),1.38(s,9H),1.16-0.99(m,6H).LC-MS=245.1[M+H] + , retention time = 1.00 min.

[0473] Compound 56-0: 3-azido-4-methylpiperidin-4-ol [ka] Compound 56-0 was prepared in the following manner. [ka] A solution of tert-butyl 6-methyl-7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (500 mg, 2.344 mmol) in MeOH (10 mL) and HO (2 mL) was treated with NaN (762 mg, 11.72 mmol) and NH Cl (251 mg, 4.69 mmol). The reaction was heated to 65 °C for 18 h. The reaction mixture was concentrated in vacuo, diluted with DCM, filtered through a phase sepa...

Claims

1. Formula Ic: 【Chemistry 3】 (In the formula, Z is N; Y １ is C(OH)CH ２ N.H. ２ and R １ is -C １～４ is alkyl; R ２ａ is -C １～４ is alkyl; R ２ｂ is hydrogen; R ３ａ is amino, -CO-C １～４ Alkyl and N, S(O) ０～２ and O; R ３ａ is unsubstituted or substituted with one or two hydroxy or amino groups; R ３ｂ , R ３ｃ , R ３ｄ and R ３ｅ is hydrogen, C １～４ Alkyl, amino, -X １ -R ３ａ , -NH-X １ -R ３ａ , hydroxy-substituted C １～４ Alkyl, C １～４ Alkoxy-substituted C １～４ Alkyl, hydroxy, halo, -X １ -CO ２ H, -X １ -CO ２ N.H. ２ , -X １ -SO ２ C １～４ Alkyl, -X １ -SO ２ N (C １～４ Alkyl) ２ and -X １ -C ３～６ -cycloalkyl; X １ is a bond and C １～４ alkylene) or a pharma- ceutically acceptable salt thereof.

2. The compound has the following structure: 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

3. 3. A pharma- ceutically acceptable salt of the compound of claim 2, wherein the pharma- ceutically acceptable salt is in the adipate form, the ratio of the compound to adipic acid being 2:

1.

4. 4. A crystalline form A of the adipate salt of the compound of claim 3, characterized by an X-ray diffraction pattern having at least three peaks at 2θ values ​​selected from 3.56, 7.15 and 17.87±0.2°2θ.

5. 4. A crystalline form B of the adipate salt of the compound of claim 3, characterized by an X-ray diffraction pattern having at least three peaks at 2θ values ​​selected from 9.40, 10.93 and 19.33±0.2°2θ.

6. 10. A pharmaceutical composition for the prevention or treatment of malaria, comprising a compound according to claim 1 or a pharma- ceutically acceptable salt thereof, optionally in combination with a second drug.

7. The pharmaceutical composition of claim 6 , wherein the second drug is selected from a kinase inhibitor, an antimalarial drug, and an anti-inflammatory drug.

8. 8. The pharmaceutical composition of claim 7, wherein the antimalarial drug is selected from proguanil, chlorproguanil, trimethoprim, chloroquine, mefloquine, lumefantrine, atovaquone, pyrimethamine-sulfadoxine, pyrimethamine-dapsone, halofantrine, quinine, quinidine, amodiaquine, amphopyroquine, sulfonamides, artemisinin, artefren, artemether, artesunate, primaquine, pyronaridine, KAE-609, and KAF-156.

9. 7. The pharmaceutical composition of claim 6, wherein the compound of claim 1 is administered prior to, simultaneously with, or after the second agent.

10. The pharmaceutical composition of claim 6 , wherein the compound is administered to a human suffering from malaria.

Images