ring A is phenyl or a five to ten membered heteroaryl ring containing, inclusive of X, one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur；

Ar1 is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein each of the aforementioned ring is substituted with Ra, Rb, and/or Rc,

wherein Ra and Rb are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,

haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl,

cyano, and hydroxy； or Ra and Rb, when on adjacent ring vertices, combine toform a C3-6

cycloalkyl, or Ra and Rb, when on the same ring vertex, combine to form oxo, and Rc is selected

from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl,

aminoalkyl, heterocyclylalkyl, heterocyclyloxy, aminocarbonyl；

Ar2 is phenyl, heteroaryl, or cycloalkyl, wherein said phenyl and heteroaryl are substituted with Rd, Re and/or Rf, wherein Rd and Re are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and Rf is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of

Rf are unsubstituted or substituted with one, two, or three substituents independently selected

from alkyl, halo, haloalkyl, and hydroxy；

R1 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl,

carboxy, alkoxycarbonyl, acylamino, aminocarbonyl·optionally substituted heteroaryl, hydroxyalkyl, cycloalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl,

sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted

heterocyclylalkyl； and

R2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano；

Y is O or S or NH or NR^g , R^g is a C1 to C3 aliphatic group；

R3 and R4 are H, C1-6 aliphatic group.

DETAILED DESCRIPTION OF THE INVENTION

Example 1: N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -1- (2-methoxyphenyl) -1H-imidazole-5-carboxamide

Step 1: Preparation of ethyl 1- (2-methoxyphenyl) -1H-imidazole-5-carboxylate

A mixture of compound 1_1A (3.32 g, 16.2 mmol, 50％purity in toluene, 1.00 eq), compound 1_1 (2.00 g, 16.24 mmol, 1.83 mL, 1 eq) , Na₂SO₄ (13.8 g, 97.4 mmol, 9.89 mL, 6.00 eq) in toluene (20 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 110 ℃ for 1 hr under N₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue as “A” . A mixture of “A” , K₂CO₃ (1.48 g, 10.7 mmol, 0.66 eq) , TosMIC (1.59 g, 8.12 mmol, 0.50 eq) in EtOH (20 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 50 ℃ for 12 hrs under N₂ atmosphere. LCMS showed compound 1_1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was quenched by with H₂O (30 mL) at 25℃, and then extracted with EtOAc (50 mL, 30 mL, 20 mL) . The combined organic layers were washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate ＝ 100/1 to 0/1) . Compound 1_2 (1.10 g, 4.47 mmol, 27.50％yield) was obtained as a brown solid.

Step 2: preparation of compound 1- (2-methoxyphenyl) -1H-imidazole-5-carboxylic acid (1_3)

A mixture of compound 1_2 (500 mg, 2.03 mmol, 1.00 eq) , LiOH^. H₂O (170 mg, 4.06 mmol, 2.00 eq) in MeOH (5 mL) and H₂O (4 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 20 ℃ for 12 hrs under N₂ atmosphere. LCMS showed compound 1_2 was consumed completely and one main peak with desired MS was detected. Diluted with H₂O 15 mL and extracted with EtOAc (20 mL, 15 mL, 10 mL) . And then the PH of the aqueous phase was adjusted to the 4-5 with HCl (2 M) at 20 ℃, extracted with EtOAc (30 mL, 20 mL, 20 mL, 10 mL) . The combined organic layers were washed with brine 15 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product (200 mg, 917 umol) was used into the next step without further purification as a yellow solid.

Step 3: Preparation of compound 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (1_5)

Add compound 1_4 (2.00 g, 10.7 mmol, 1.00 eq) and compound 1_4A (977 mg, 10.7 mmol, 1.00 eq) in the 250ml three-neck flask. And then POCl₃ (8 mL) was slowly poured into the mixture. The mixture was stirred at 75 ℃ for 1 hr. LCMS showed compound 1_4 was consumed completely and one main peak with desired MS was detected. The reaction mixture was poured into the ice water 30 mL at 0 ℃ and stirred at 0 ℃ for 2 hrs. And then filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with EtOAc 10 mL at 25 ℃ for 1 hr. The product was dried for 2 hrs at 80-100 ℃ in the drying oven. Compound 1_5 (2.10 g, 8.69 mmol, 81.1％yield) was obtained as a white solid.

Step 4 preparation of N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -1- (2-methoxyphenyl) -1H-imidazole-5-carboxamide (1)

A mixture of compound 1_3 (200 mg, 917 umol, 1.00 eq) , DIPEA (474 mg, 3.67 mmol, 639 uL, 4.00 eq) , compound 1_5 (377 mg, 1.56 mmol, 1.70 eq) , HATU (523 mg, 1.37 mmol, 1.50 eq) in DMF (4 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 50 ℃ for 12 hrs under N₂ atmosphere. LCMS showed compound 1_3 was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (30 mL, 20 mL, 10 mL) . The combined organic layers were washed with brine 20 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 (80*40mm*3um) ； mobile phase: [water (NH₄HCO₃) -ACN] ； B％: 40％-60％, 8 min) . 1 (95 mg, 215 umol, 23.5％yield) was obtained as a yellow solid.

¹H NMR : (400 MHz, CDCl₃)

δ 11.3 (s, 1H) , 8.27 (s, 1H) , 7.77 (s, 1H) , 7.50-7.73 (m, 1H) , 7.33 (d, J ＝ 6.4 Hz, 1H) , 7.24-7.25 (m, 1H) , 7.06-7.12 (m, 2H) , 6.92 (d, J ＝ 9.2 Hz, 2H) , 5.41 (s, 2H), 3.76 (s, 3H) .

Example 2: N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -1- (2-chlorophenyl) -1H-imidazole-5-carboxamide (2)

Step 1: Preparation of ethyl 1- (2-chlorophenyl) -1H-imidazole-5-carboxylate (2_2)

A mixture of compound 1_1A (3.20 g, 15.7 mmol, 50％purity in toluene, 1.00 eq), compound 2_1 (2.00 g, 15.7 mmol, 1.65 mL, 1.00 eq) , Na₂SO₄ (13.4 g, 94.1 mmol, 6.00 eq) in toluene (20 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 110 ℃ for 1 hr under N₂ atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue as “A” . A mixture of “A” , K₂CO₃ (1.43 g, 10.4 mmol, 0.66 eq) , TosMIC (1.53 g, 7.84 mmol, 0.50 eq) in EtOH (20 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 50 ℃ for 12 hrs under N₂ atmosphere. LCMS showed compound 2_1 was consumed completely and one main peak with desired MS was detected. The reaction mixture was quenched by with H₂O (30 mL) at 25℃, and then extracted with EtOAc (50 mL, 30 mL, 20 mL) . The combined organic layers were washed with brine (30 mL) , dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO₂, Petroleum ether/Ethyl acetate ＝ 100/1 to 0/1) . Compound 2_2 (1.20 g, 4.79 mmol, 30.5％yield) was obtained as a yellow oil.

Step 2: Preparation of 1- (2-chlorophenyl) -1H-imidazole-5-carboxylic acid (2_3)

A mixture of compound 2_2 (600 mg, 2.39 mmol, 1.00 eq) , LiOH^. H₂O (201 mg, 4.79 mmol, 2.00 eq) in MeOH (3 mL) and H₂O (2.5 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 25 ℃ for 12 hrs under N₂ atmosphere. LCMS showed compound 2_2 was consumed completely and one main peak with desired MS was detected. Diluted with H₂O 15 mL and extracted with EtOAc (20 mL, 15 mL, 10 mL) . And then the PH of the aqueous phase was adjusted to the 5-6 with HCl (2 M) at 20 ℃, extracted with EtOAc (30 mL, 20 mL, 20 mL, 10 mL) . The combined organic layers were washed with brine 15 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product (400 mg, 1.80 mmol) was used into the next step without further purification as a yellow solid.

¹H NMR : ET51185-16-P1D3 (400 MHz, DMSO)

δ 12.8 (s, 1H) , 8.00 (s, 1H) , 7.75 (s, 1H) , 7.64 (d, J ＝ 1.2 Hz, 1H) , 7.50-7.55 (m, 3H) .

Step 3: Preparation of N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -1- (2-chlorophenyl) -1H-imidazole-5-carboxamide (2)

A mixture of compound 2_3 (200 mg, 898 umol, 1.00 eq) , DIPEA (464 mg, 3.59 mmol, 626 uL, 4.00 eq) , compound 1_5 (304 mg, 1.26 umol, 1.40 eq) , HATU (512 mg, 1.35 mmol, 1.50 eq) in DMF (4 mL) was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 50 ℃ for 12 hrs under N₂ atmosphere. LCMS showed compound 2_3 was consumed completely and one main peak with desired MS was detected. The reaction mixture was diluted with H₂O 20 mL and extracted with EtOAc (30 mL, 20 mL, 10 mL) . The combined organic layers were washed with brine 20 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex C18 (80*40mm*3um) ； mobile phase: [water (NH₄HCO₃) -ACN] ； B％: 30％-60％, 8 min) . 2 (95 mg, 213 umol, 23.7％yield) was obtained as a yellow solid.

¹H NMR : ET51185-17-P1B3 (400 MHz, MeOD)

δ 12.4 (s, 1H) , 8.54 (s, 1H) , 7.79 (s, 1H) , 7.58 (d, J ＝ 7.6 Hz, 1H) , 7.44-7.51(m, 3H) , 7.25-7.44 (m, 2H) , 6.92 (d, J ＝ 8.8 Hz, 2H) , 5.42 (s, 2H) .

Example 3: 5- ( ( (4-chlorophenyl) amino) methyl) -1, 3, 4-thiadiazol-2-amine (3)

Step 1: preparation of 3- (2-methoxyphenyl) isonicotinic acid (3_4)

To a solution of compound 3_5 (2.00 g, 9.90 mmol, 1.00 eq) and (2-methoxyphenyl) boronic acid (2.26 g, 14.9 mmol, 1.50 eq) in 1, 4-dioxane (10.0 mL) and H₂O (10.0 mL) was added Na₂CO₃ (1.15 g, 10.9 mmol, 1.10 eq) and Pd(PPh₃) ₄ (1.14 g, 990 umol, 0.10 eq) . The mixture was degassed and purged with N₂ for 3 times, and then the mixture was stirred at 100℃ for 12 hrs under N₂ atmosphere. LC-MS (ET51179-2-P1A, compound 3_5: RT ＝ 0.161 min, compound 3_4A: RT ＝ 0.509 min) showed ～16.9％of compound 3_5 remained. Several new peaks were shown on LC-MS and ～13.9％of desired compound was detected. The mixture was cooled to room temperature and diluted with water 20.0 mL. The mixture was extracted with EtOAc (2 x 20.0 mL) . The aqueous layer was acidified to pH 6 with HC1 (1.00 M) , and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 3_4A (0.50 g, crude, ～68％purity) was obtained as a yellow solid. LCMS (compound 3_4A: RT ＝ 0.474 min) .

Step 2: Preparation of methyl (4-chlorophenyl) glycinate (3_3)

To a solution of compound 3_1 (5.00 g, 39.2 mmol, 1.00 eq) in acetone (35.0 mL) was added K₂CO₃ (16.3 g, 118 mmol, 3.00 eq) and compound 3_1A (6.60 g, 43.1 mmol, 1.10 eq) . The mixture was stirred at 60℃ for 12 hrs under N₂ atmosphere. LC-MS (compound 3_2: RT ＝ 0.634 min) showed ～69.7％of desired compound was detected. The reaction mixture was quenched by addition H₂O 50.0 mL, and then extracted with EtOAc (15.0 mL x 3) . The combined organic layers were washed with brine 15.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 3_2 (7.25 g, 29.1 mmol, 74.2％yield, 80.1％purity) was obtained as a yellow solid.

¹HNMR: ET51179-1-P1A (400 MHz, CDCl₃)

δ 7.15 (d, J ＝ 8.8 Hz, 2H) , 6.54 (d, J ＝ 8.8 Hz, 2H) , 3.89 (s, 2H) , 3.79 (s, 3H) .

Step 3: Preparation of (4-chlorophenyl) glycine (3_3)

To a solution of compound 3_2 (7.25 g, 36.3 mmol, 1.00 eq) in H₂O (50.8 mL) was added LiOH. H₂O (3.05 g, 72.6 mmol, 2.00 eq) . The mixture was stirred at 100℃ for 12 hrs. LC-MS (ET51179-3-P1A, compound 3_3: RT ＝ 0.548 min) showed compound 3_2 was consumed completely and one main peak with desired mass was detected. The reaction mixture was extracted with EtOAc (20.0 mL) and discarded the EtOAc phase. The aqueous layer was acidified to pH 6 with HC1 (1.00 M) , and extracted with EtOAc (50.0 mL x 3) . The combined organic layers were washed with brine 20.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 3_3 (5.10 g, 27.5 mmol, 75.7％yield) was obtained as a yellow solid.

Step 4: Preparation of 5- ( ( (4-chlorophenyl) amino) methyl) -1, 3, 4-thiadiazol-2-amine (3_4)

POCl₃ (33.0 g, 215 mmol, 20.0 mL, 7.99 eq) was added to a mixture of compound 3_3 (5.00 g, 26.9 mmol, 1.00 eq) and compound 3_3A (2.46 g, 26.9 mmol, 1.00 eq) . The reaction mixture was stirred at 65℃ under N₂ atmosphere for 1 hr. TLC (Petroleum ether/Ethyl acetate ＝ 0: 1, compound 3_3: RT ＝ 0.07, compound 3_4: RT ＝ 0.43) indicated compound 3_3 was consumed completely and one main new spot formed. The reaction was messy according to TLC. The mixture was poured into ice-water 100 mL and stirred at 0 ℃ for 20 min, and extracted with EtOAc (10.0 mL x 3) . The combined organic layers were dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was purified by reversed-phase HPLC (0.1％NH₄HCO₃ condition) . Compound 3_4 (3.00 g, 12.5 mmol, 46.3％yield) was obtained as a yellow solid.

¹HNMR: (400 MHz, DMSO)

δ 7.10 (d, J ＝ 8.8 Hz, 2H) , 7.03 (s, 2H) , 6.63 (d, J ＝ 8.8 Hz, 2H) , 6.53 (t, J ＝6.4 Hz, 1H) , 4.39 (d, J ＝ 6.4 Hz, 2H) .

Step 5: Preparation of 5- ( ( (4-chlorophenyl) amino) methyl) -1, 3, 4-thiadiazol-2-amine (3)

To a solution of compound 3_4 (150 mg, 623 umol, 1.00 eq) and compound 3_4A (143 mg, 623 umol, 1.00 eq) in DCM (1.5 mL) was added DIPEA (161 mg, 1.25 mmol, 2.00 eq) and HATU (355 mg, 935 umol, 1.50 eq) . The mixture was stirred for 12 hrs at 25℃ under nitrogen. LC-MS (ET51179-18-P1A, 3: RT ＝ 0.608 min) showed compound 3_4 was consumed completely and one main peak with desired mass was detected. The reaction mixture was diluted with H₂O 20.0 mL and extracted with EtOAc (10.0 mL x 3) . The combined organic layers were washed with brine 10.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate ＝ 1/5) . TLC (Petroleum ether/Ethyl acetate ＝ 1/5, 3: R_f ＝ 0.39 min) . Then purified by prep-HPLC (column: Phenomenex Luna 80*30mm*3um； mobile phase: [water (HCl) -ACN] ； B％: 35％-65％, 8min) . Finally, 18 mg (99.2％purity) of product as yellow solid.

¹HNMR: (400 MHz, DMSO)

δ 13.03 (brs, 1H) , 8.78 (d, J ＝ 5.2 Hz, 1H) , 8.69 (s, 1H) , 7.76 (br d, J ＝ 4.8 Hz, 1H), 7.30-7.44 (m, 2H) , 7.01 -7.19 (m, 3H) , 6.93 (d, J ＝ 8.4 Hz, 1H) , 6.63 (d, J ＝ 8.8 Hz, 2H) , 4.62 (s, 2H) , 3.41 (s, 3H) .

Example 4:

Step 1: Preparation of methyl (4-chlorophenyl) glycinate

To a solution of compound 4_1 (5.00 g, 39.2 mmol, 1.00 eq) in acetone (35.0 mL) was added K₂CO₃ (16.3 g, 118 mmol, 3.00 eq) and compound 4_1A (6.60 g, 43.1 mmol, 1.10 eq) . The mixture was stirred at 60℃ for 12 hrs under N₂ atmosphere. LCMS (4_2: RT ＝ 0.634 min) showed ～69.7％of desired compound was detected. The reaction mixture was quenched by addition H₂O 50.0 mL, and then extracted with EtOAc (15.0 mL x 3) . The combined organic layers were washed with brine 15.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 4_2 (7.25 g, 29.1 mmol, 74.2％yield, 80.1％purity) was obtained as a yellow solid.

¹HNMR: ET51179-1-P1A (400 MHz, CDCl₃)

Step 2: preparation of methyl N- (4-chlorophenyl) -N-methylglycinate (4_3)

To a solution of compound 4_2 (3.50 g, 17.5 mmol, 1.00 eq) in DMF (24.5 mL) were added K₂CO₃ (7.27 g, 52.6 mmol, 3.00 eq) and MeI (4.98 g, 35.1 mmol, 2.00 eq) , and the mixture was stirred for 12 hrs at 20℃. LCMS (4_2: RT ＝ 0.955 min, compound 4_3: RT ＝ 1.004 min) showed ～1.63％of compound 4_3 remained. One of new peaks was shown on LC-MS with desired compound was detected. The reaction mixture was poured into water 30.0 mL and extracted with ethyl acetate (15.0 mL x 3) . The extract was washed with brine 10.0 mL and dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 4_3 (2.50 g, 11.7 mmol, 66.7％yield) was obtained as a yellow solid.

Step 3: Preparation of N- (4-chlorophenyl) -N-methylglycine (4_4)

To a solution of compound 4_3 (1.50 g, 7.02 mmol, 1.00 eq) in H₂O (10.5 mL) was added LiOH. H₂O (589 mg, 14.04 mmol, 2.00 eq) . The mixture was stirred at 100℃ for 12 hrs. TLC (Petroleum ether/Ethyl acetate ＝ 0: 1, product: R_f ＝ 0.1) indicated compound 4_3 was consumed completely and one new spot formed. The reaction mixture was extracted with EtOAc (10.0 mL) and discarded the EtOAc phase. The aqueous layer was acidified to pH 6 with HC1 (1.00 M), and extracted with EtOAc (10.0 mL x 3) . The combined organic layers were washed with brine 10.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The crude product was used into the next step without further purification. Compound 4_4 (1.30 g, 6.51 mmol, 92.8％yield) was obtained as a yellow solid.

Step 4: Preparation of 5- ( ( (4-chlorophenyl) (methyl) amino) methyl) -1, 3, 4-thiadiazol-2-amine (4_5)

POCl₃ (6.60 g, 43.0 mmol, 4.00 mL) was added to a mixture of compound 4_4 (1.00 g, 5.01 mmol, 1.00 eq) and compound 4_4A (457 mg, 5.01 mmol, 1.00 eq) . The reaction mixture was stirred at 75℃ under N₂ atmosphere for 4 hrs. LCMS (compound 4_5: RT ＝ 0.568 min) showed compound 4_4 was consumed completely and one of main peaks with desired MS was detected. The mixture was poured into ice-water 20.0 mL and stirred at 0℃ for 20 min, and extracted with EtOAc (15.0 mL x 3) . The combined organic layers were washed with brine 10.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate ＝ 0/1) . TLC (Petroleum ether/Ethyl acetate＝0/1) . Compound 4_5 (0.20 g, 785 umol, 15.7％yield) was obtained as a yellow solid.

Step 5: preparation of N- (5- ( ( (4-chlorophenyl) (methyl) amino) methyl) -1, 3, 4-thiadiazol-2-yl) -3- (2-methoxyphenyl) isonicotinamide (4)

To a solution of compound 4_5 (0.20 g, 785 umol, 1.00 eq) and compound 4_5A (180 mg, 785 umol, 1.00 eq) in DCM (2.00 mL) was added DIPEA (203 mg, 1.57 mmol, 2.00 eq) and HATU (448 mg, 1.18 mmol, 1.50 eq) . The mixture was stirred for 12 hrs at 25℃ under nitrogen. LCMS (4: RT ＝ 0.635 min) showed compound 4_5 was consumed completely and one of peaks with desired MS was detected. The reaction mixture was diluted with H₂O 20.0 mL and extracted with EtOAc (10.0 mL x 3) . The combined organic layers were washed with brine 10.0 mL, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-TLC (SiO₂, Petroleum ether/Ethyl acetate ＝ 1: 5, 4: R_f ＝ 0.39) . Then purified by prep-HPLC (column: Phenomenex Luna 80 x 30mm x 3um； mobile phase: [water (HCl) -ACN] ； B％:35％-65％, 8min) . 4 (3.00 mg, 5.97 umol, 0.76％yield, 100％purity, HCl) was obtained as a yellow solid.

¹HNMR: ET51179-19-P1A (400 MHz, DMSO)

δ 13.05 (br s, 1H) , 8.73 (d, J ＝ 5.2 Hz, 1H) , 8.64 (s, 1H) , 7.68 (br d, J ＝ 4.8 Hz, 1H), 7.30 -7.43 (m, 2H) , 7.20 (d, J ＝ 8.8 Hz, 2H) , 7.05 (t, J ＝ 7.6 Hz, 1H) , 6.93 (d, J ＝ 8.0 Hz, 1H) , 6.82 (d, J ＝ 9.2 Hz, 2H) , 4.90 (s, 2H) , 4.34 -4.44 (m, 2H) , 3.40 (s, 3H), 2.97 (s, 3H) .

Example 5: N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide (5)

Step 1: methyl 4-chloro-6-methylnicotinate

To a solution of 4-chloro-6-methylnicotinic acid (4.0 g, 23 mmol) in DMF (40 mL) was added K₂CO₃ (4.8 g, 35 mmol) and MeI (4.3 g, 30 mmol) and the reaction mixture was stirred at room temperature for 6 hours. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness to give the title compound (3.5 g, 82％yield) as light yellow solid. LC/MS (ESI) (m/z) : 186 (M+H) ⁺.

Step 2: methyl 4- (2-methoxyphenyl) -6-methylnicotinate

To a mixture of methyl 4-chloro-6-methylnicotinate (3.0 g, 16 mmol) and (2-methoxyphenyl) boronic acid (5.0 g, 32 mmol) in 1, 4-dioxane (24 mL) and H₂O (3 mL) was added K₂CO₃ (4.4 g, 32 mmol) followed by Pd (dppf) Cl₂ (1.1 g, 1.6 mmol) under N₂ atmosphere. The mixture was degassed under N₂ atmosphere for three times and stirred at 80 ℃ for 16 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness. The residue was purified by flash chromatography (silicagel, 0 -20％of EtOAc in PE) to give the title compound (4.0 g, 82％yield) as yellow solid. LC/MS (ESI) (m/z) : 258 (M+H) ⁺.

Step 3: 4- (2-methoxyphenyl) -6-methylnicotinic acid

To a solution of methyl 4- (2-methoxyphenyl) -6-methylnicotinate (4 g, 15.6 mmol) in MeOH (20 mL) and H₂O (20 mL) was added NaOH (1 g, 23.4 mmol) and the mixture was stirred at room temperature for 8 hours. The mixture was acidified with 1N aq. HCl to pH～3 and extracted with DCM (2 x 20 mL) . The combined organic layers were washed with brine, dried over anhydrous Na₂SO₄, filtered and concentrated to dryness to give the title compound (3.6 g, 94.5％yield) as yellow solid. LC/MS (ESI) (m/z) : 244 (M+H) ⁺.

Step 4: 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine

A mixture of 2- (4-chlorophenoxy) acetic acid (5 g, 26.8 mmol) and hydrazinecarbothioamide (2.4 g, 26.8 mmol) in POCl₃ (20 mL) was stirred at 75 ℃ under N₂ atmosphere for 1 hour. The mixture was poured into ice-water and stirred at 0 ℃ for 20 min. The slurry was filtered and the filter cake was dried under vacuum to give the title compound (4.2 g, 65.0％yield) as yellow solid. LC/MS (ESI) (m/z) : 242 (M+H) ⁺

Step 5: N- (5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-yl) -4- (2-methoxyphenyl) -6-methylnicotinamide (5)

To a solution of 4- (2-methoxyphenyl) -6-methylnicotinic acid (500 mg, 2.05 mmol) in DCM (5 mL) was added Oxalyl chloride (0.2 mL, 2.36 mmol) at 0 ℃ and the mixture was stirred at room temperature for 1 hour. Then a mixture of 5- ( (4-chlorophenoxy) methyl) -1, 3, 4-thiadiazol-2-amine (496 mg, 2.05 mmol) and TEA(0.6 mL, 4.1 mmol) in DCM (5 mL) was added drop-wisely to the mixture at 0 ℃ and the resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness and the residue was purified by prep-HPLC to give the title compound (65 mg, 6.8％yield) as white solid. ¹H NMR (400 MHz, DMSO) δ 13.03 (s, 1H) , 8.69 (s, 1H) , 7.41 -7.34 (m, 4H) , 7.31 (s, 1H) , 7.11 -7.05 (m, 3H) , 6.95 (d, J ＝ 8.2 Hz, 1H) , 5.50 (s, 2H) , 3.43 (s, 3H) , 2.57 (s, 3H) . LC/MS (ESI) (m/z) : 467 (M+H) ⁺ .

Example 6: Biological evaluation

The ability of the compounds to inhibit ATPase activity of PolQ (1-899) was determined using the assay described below.

PolQ ATPase activity was determined by ADP-Glo assay. 10-point dilution series of compounds were used in a 384 well format for the inhibition assays. Poltheta (1-899) (1 nM) in assay buffer (20 mM Tris HC1 (pH 8.0) , 80 mM KC1, 10 mM MgCl2, 1 mM DTT, 0.01％BSA, 0.01％Tween, 5％glycerol) was transferredto the test wells (20 uL) , except the low control wells (20 uL of assay buffer was added to the low control wells) . The plate was then incubated at room temperature for 30 min. An equal volume (20 uL) of 100 uM ATP, 150 nM ssDNA containing 50 thymine bases in assay buffer was added to all the test wells. The plates were covered and left to incubate for 1 hour at room temperature before the addition of the ADP Glo detection reagents. After 60 min incubation, transfer 5 ul reaction mix to another 384-well plate and add 5 μL ADP Glo and plates incubated for 60 minutes before addition of 10 μL kinase detection reagent. After the addition of the kinase detection reagent, the plates were covered and incubated for 60 minutes and read luminescence on Envision

Percent inhibition was calculated as follows: 100- ( (Compound-Min) / (Max-Min) *100) where “Max” is the high control (DMSO) and “Min” is the no enzyme control. IC50 values were calculated using a four-parameter logistic curve fit using the following formula: LowerBound+ ( (UpperBound-LowerBound) / (1+ ( (IC50/x) ^Hill) ) )

Claims

Poly theta inhibitor
Wherein:
X is -N-or -C-；
ring A is phenyl or a five to ten membered heteroaryl ring containing, inclusive of X, one to four heteroatoms independently selected from nitrogen, oxygen, or sulfur；
Ar1 is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein each of the aforementioned ring is substituted with Ra, Rb, and/or Rc,
wherein Ra and Rb are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy,
haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl,
cyano, and hydroxy； or Ra and Rb, when on adjacent ring vertices, combine to form a C3-6
cycloalkyl, or Ra and Rb, when on the same ring vertex, combine to form oxo, and Rc is selected
from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl,
aminoalkyl, heterocyclylalkyl, heterocyclyloxy, aminocarbonyl；
Ar2 is phenyl, heteroaryl, or cycloalkyl, wherein said phenyl and heteroaryl are substituted with Rd, Re and/or Rf, wherein Rd and Re are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and Rf is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of
Rf are unsubstituted or substituted with one, two, or three substituents independently selected
from alkyl, halo, haloalkyl, and hydroxy；
R1 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl,
carboxy, alkoxycarbonyl, acylamino, aminocarbonyl · optionally substituted heteroaryl, hydroxyalkyl, cycloalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl,
sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted
heterocyclylalkyl； and
R2 is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano；
Y is O or S or NH or NR^g , R^g is a C1 to C3 aliphatic group；
R3 and R4 are H, C1-6 aliphatic group.
The compound of claim 1, wherein:
X is -N-or -C-；
alk is alkylene；
ring A is phenyl or a five or six membered heteroaryl ring containing, inclusive of X, one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur；
Ar¹ is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein each of the aforementioned ring is substituted with R^a, R^b, and/or R^c, wherein R^a and R^b are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl, cyano, and hydroxy, and R^c is selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and
aminocarbonyl；
Ar² is phenyl, heteroaryl, or cycloalkyl, wherein said phenyl and heteroaryl are substituted with R^d, R^e and/or R^f, wherein R^d and R^e are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and R^f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of R^f are unsubstituted or substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, and hydroxy；
R¹ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, cyanoalkyl, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl · optionally substituted heteroaryl, hydroxyalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted
heterocyclylalkyl； and
R² is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano； or
a pharmaceutically acceptable salt thereof.
The compound of claim 1, wherein:
X is -N-or -C-；
alk is alkylene；
ring A is phenyl or a five or six membered heteroaryl ring containing, inclusive of X, one to three heteroatoms independently selected from nitrogen, oxygen, or sulfur；
Ar¹ is phenyl, heteroaryl, heterocyclyl, bicyclic heterocyclyl, bridged heterocyclyl, or spiroheterocyclyl, wherein each of the aforementioned ring is substituted with R^a, R^b, and/or R^c, wherein R^a and R^b are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, cycloalkyloxy, acyl, acylamino, monoalkylamino, dialkylamino, alkylsulfonyl, cyano, and hydroxy, and R^c is selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and
aminocarbonyl；
Ar² is phenyl, heteroaryl, or cycloalkyl, wherein said phenyl and heteroaryl are substituted with R^d, R^e and/or R^f, wherein R^d and R^e are independently selected from hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, and cyano and R^f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of R^f are unsubstituted or substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, and hydroxy；
R¹ is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkoxy, hydroxy, cyano, carboxy, alkoxycarbonyl, acylamino, aminocarbonyl · optionally substituted heteroaryl, hydroxyalkyl, hydroxyalkynyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, sulfonylalkyl,
aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted
heterocyclylalkyl； and
R² is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, or cyano； or
a pharmaceutically acceptable salt thereof.
The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof wherein the compound has a structure of formula (Ia or Ib) :
The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof wherein ring A is phenyl, pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, triazolyl, imidazo [l, 2-a] pyridinyl, [l, 2, 3] triazolo [l, 5-a] pyridinyl, imidazo [l, 5-a] pyridinyl, pyrrolo [2, 3 -bjpyridinyl, pyrrolo [3 , 2-b] pyridinyl, pyrazolo [1 , 5-a] pyridinyl, [1 , 2, 4] triazolo [1, 5-a] pyridinyl, 1, 6-naphthyridinyl, or 1, 7-naphthyridinyl.
The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof wherein ring A is a nine or ten membered heteroaryl ring.
The compound of claim 6, or a pharmaceutically acceptable salt thereof wherein ring A is imidazo [l, 2-a] pyridinyl, [l, 2, 3] triazolo [l, 5-a] pyridinyl, imidazo [l, 5-a] pyridinyl, pyrrolo [2, 3 -bjpyridinyl, pyrrolo [3 , 2-b] pyridinyl, pyrazolo [1 , 5-a] pyridinyl, [1 , 2, 4] triazolo [1, 5-ajpyridinyl, 1, 6-naphthyridinyl, or 1, 7-naphthyridinyl.
The compound of any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof wherein ring A is a five or six membered heteroaryl ring.
The compound of claim 8, or a pharmaceutically acceptable salt thereof wherein ring A is pyridinyl, pyridazinyl, pyrimidinyl, imidazolyl, pyrazolyl, or triazolyl.
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is:
The compound of any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof wherein ring A is phenyl.
The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof wherein Ar¹ is heterocyclyl substituted with R^a, R^b, and/or R^c.
The compound of claim 20, or a pharmaceutically acceptable salt thereof wherein Ar¹ is piperidinyl, piperazinyl, morpholinyl, homomorpholinyl, 2-oxopiperazinyl, 2-oxohomopiperazinyl, tetrahydropyranyl, 3, 6-dihydro-2H-pyranyl, 2-oxo-l, 2-dihydropyridinyl, thiomorpholinyl, or 1, 1-dioxothiomorpholinyl substituted with R^a, R^b, and/or R^c.
The compound of claim 20, or a pharmaceutically acceptable salt thereof wherein Ar¹ is piperidin-l-yl, piperazin-l-yl, morpholin-4-yl, homomorpholin-4-yl, 3-oxopiperazin-l-yl, 3-oxohomopiperazin-l-yl, 5-oxohomopiperazin-l-yl, tetrahydropyran-4-yl, 3, 6-dihydro-2H-pyran-4-yl, 6-oxo-l, 6-dihydropyridin-3-yl, 6-oxo-l, 6-dihydropyridin-4-yl, thiomorpholin-4-yl, or l, l-dioxothiomorpholin-4-yl substituted with R^a, R^b, and/or R^c.
The compound of claim 20, or a pharmaceutically acceptable salt thereof wherein Ar¹ is morpholin-4-yl substituted with R^a, R^b, and/or R^c.
The compound of any one of claims 20 to 23, or a pharmaceutically acceptable salt thereof wherein R^a is hydrogen or alkyl, R^b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy, and R^c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
The compound of any one of claims 20 to 23, or a pharmaceutically acceptable salt thereof wherein R^a and R^b, when on adjacent ring vertices, combine to form a cyclopropyl or cyclobutyl ring, and R^c is hydrogen.
The compound of any one of claims 20 to 23, or a pharmaceutically acceptable salt thereof wherein Ar¹ is substituted with R^b and/or R^c wherein R^b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R^c is hydrogen, methyl, ethyl, fluoro,
difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy,
trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
The compound of claim 20, or a pharmaceutically acceptable salt thereof wherein Ar¹ is morpholin-4-yl, homomorpholin-4-yl, 2-methylmorpholin-4-yl, 3-methylmorpholin-4-yl, 3R-methylmorpholin-4-yl, 3S-methylmorpholin-4-yl, 3-oxopiperazin-l-yl, 4-methyl-3-oxo-piperazin-l-yl, 2-methyl-3-oxopiperazin-l-yl, 6-methyl-3-oxopiperazin-l-yl, 5-methyl-3-oxopiperazin-l-yl, 3-oxohomopiperazin-l-yl, 5-oxohomopiperazin-l-yl, 4-dimethylaminocarbonylpiperazin-l-yl, tetrahydropyran-4-yl, 3, 6-dihydro-2H-pyran-4-yl, 4- (2-hydroxyethyl) -3-oxopiperazin-l-yl, 6-oxo-l, 6-dihydropyridin-4-yl, 6-oxo-l, 6-dihydropyridin-3-yl, l-methyl-6-oxo-l, 6-dihydropyri din-3-yl, 4- (2-morpholin-4-ylethyl) -3-oxopiperazin-l-yl, 4-methylcarbonylpiperazin-l-yl, 4-methylsulfonylpiperazin-l-yl, l, l-dioxothiomorpholin-4-yl, or 4, 4-difluoropiperidin-1 -yl.
The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof wherein wherein Ar¹ is bicyclic heterocyclyl substituted with R^a, R^b, and/or R^c.
The compound of claim 28, or a pharmaceutically acceptable salt thereof wherein Ar¹ is 6-oxohexahydropyrrolo [l, 2-a] pyrazin-2 (lH) -yl or 2, 3-dihydro-4H-benzo [b] [l, 4] oxazin-4-yl, each ring substituted with R^a, R^b, and/or R^c.
The compound of claim 28, or a pharmaceutically acceptable salt thereof wherein Ar¹ is selected from the group consisting of 6-oxohexahydropyrrolo [l, 2-a] pyrazin-2 (lH) -yl 3-oxo-3, 4-dihydro-2H-benzo [b] [l, 4] oxazin-8-yl, benzo [d] [l, 3] dioxol-4-yl, (3, 4-dihydro-2H-l, 4-benzoxazin-8-yl) , [5H, 6H, 7H-pyrazolo [l, 5-a] pyrimidin-4-yl] and 2, 3-dihydro-4H-benzo [b] [l, 4] oxazin-4-yl, each ring substituted with R^a, R^b, and/or R^c.
The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof wherein R^a is hydrogen, R^b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy, and R^c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and
aminocarbonyl.
The compound of any one of claims 28 to 30, or a pharmaceutically acceptable salt thereof wherein Ar¹ is substituted with R^b and/or R^c wherein R^b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R^c is hydrogen, methyl, ethyl, fluoro,
difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy,
trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof wherein Ar¹ is spiroheterocyclyl substituted with R^a, R^b, and/or R^c.
The compound of claim 33, or a pharmaceutically acceptable salt thereof wherein Ar¹ is 4-oxa-7-azaspiro [2.5] octan-7-yl substituted with R^a, R^b, and/or R^c.
The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof wherein Ar¹ is substituted with R^b and/or R^c wherein R^b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R^c is hydrogen, methyl, ethyl, fluoro, difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof wherein Ar¹ is phenyl substituted with R^a, R^b, and/or R^c.
The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein
Ar¹ is
The compound of claim 36 or claim 37, or a pharmaceutically acceptable salt thereof wherein R^a is hydrogen or alkyl, R^b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy, and R^c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
The compound of any one of claims 36 to 38, or a pharmaceutically acceptable salt thereof wherein Ar¹ is substituted with R^b and/or R^c wherein R^b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R^c is hydrogen, methyl, ethyl, fluoro,
difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy,
trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein
Ar¹ is
The compound of claim 36, or a pharmaceutically acceptable salt thereof wherein Ar¹ is phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2, 4-dimethoxyphenyl, 2-chlorophenyl, 2-cyanophenyl, or 2-cyclopropyl -oxyphenyl.
The compound of claim 36, or a pharmaceutically acceptable salt thereof wherein Ar¹ is 2-methoxyphenyl.
The compound of claim 36, or a pharmaceutically acceptable salt thereof wherein Ar¹ is 3-methoxyphenyl.
The compound of claim 36, or a pharmaceutically acceptable salt thereof wherein Ar¹ is 2, 4-dimethoxyphenyl.
The compound of any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof wherein Ar¹ is heteroaryl substituted with R^a, R^b, and/or R^c.
The compound of claim 45, or a pharmaceutically acceptable salt thereof wherein Ar¹ is benzo [c] [l, 2, 5] thiadiazolyl, benzo [d] oxazolyl, liT-indazolyl, substituted with R^a, R^b, and/or R^c where R^a is hydrogen or alkyl, R^b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy, and R^c is selected from hydrogen alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
The compound of claim 45, or a pharmaceutically acceptable salt thereof wherein Ar¹ is pyridinyl, pyrimidinyl, pyrazolyl, pyrrolyl, imidazolyl, or triazolyl substituted with R^a, R^b, and/or R^c where R^a is hydrogen or alkyl, R^b is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, acyl, alkylsulfonyl, cyano, or hydroxy, and R^c is selected from alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, alkoxyalkyl, aminoalkyl, heterocyclylalkyl, and aminocarbonyl.
The compound of any one of claims 45 to 47, or a pharmaceutically acceptable salt thereof wherein Ar¹ is substituted with R^b and/or R^c wherein R^b is hydrogen, methyl, fluoro, cyano, methylsulfonyl, or methylcarbonyl and R^c is hydrogen, methyl, ethyl, fluoro,
difluoromethyl, trifluoromethyl, trifluoroethyl, methoxy, ethoxy, difluoromethoxy,
trifluoromethoxy, trifluoroethoxy, hydroxy, 2-hydroxyethyl, 2-methoxyethyl, 2-aminoethyl, 2-morpholin-l-yl ethyl, -CONH2, methylaminocarbonyl, or dimethylaminocarbonyl.
The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof wherein Ar² is phenyl substituted with R^d, R^e and/or R^f.
The compound of claim 49, or a pharmaceutically acceptable salt thereof wherein R^d is hydrogen, R^e is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano and R^f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of R^f are unsubstituted or substituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, and hydroxy.
The compound of claim 49, or a pharmaceutically acceptable salt thereof wherein R^f is cycloalkyl optionally substituted with cyano.
The compound of claim 49, or a pharmaceutically acceptable salt thereof wherein Ar² is phenyl, 4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 2-chloro-4-fluorophenyl, 4-cyanophenyl, 4-bromophenyl, 4-oxetan—3-ylphenyl, 4-chloro-3-methoxyphenyl, 4-cyclopropylphenyl, or 4-oxazol-2-ylphenyl.
The compound of any one of claims 49 to 51, or a pharmaceutically acceptable salt thereof wherein Ar² is
The compound of claim 49, or a pharmaceutically acceptable salt thereof wherein Ar² is 4-fluorophenyl.
The compound of claim 49, or a pharmaceutically acceptable salt thereof wherein Ar² is 4-chlorophenyl.
The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof wherein Ar² is heteroaryl substituted with R^d, R^e and/or R^f.
The compound of claim 56, or a pharmaceutically acceptable salt thereof wherein R^d is hydrogen, R^e is hydrogen, alkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, or cyano and R^f is selected from hydrogen, alkyl, cycloalkyl, halo, haloalkyl, alkoxy, haloalkoxy, hydroxy, cyano, cyanomethyl, aminocarbonylmethyl, heteroaryl, and heterocyclyl, wherein said heteroaryl and heterocyclyl of R^f are unsubstituted orsubstituted with one, two, or three substituents independently selected from alkyl, halo, haloalkyl, and hydroxy.
The compound of claim 56, or a pharmaceutically acceptable salt thereof wherein R^f is cycloalkyl optionally substituted with cyano.
The compound of any one of claims 56 to 58, or a pharmaceutically acceptable salt thereof wherein Ar² is heteroaryl selected from pyridinyl or pyrimidinyl.
The compound of any one of claims 56 to 58, or a pharmaceutically acceptable salt thereof wherein Ar² is
The compound of any oen of claims 56 to 58, or a pharmaceutically acceptable salt thereof wherein Ar² is
The compound of any one of claims 1 to 48, or a pharmaceutically acceptable salt thereof wherein Ar² is cycloalkyl.
The compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof wherein R¹ is hydrogen, cyano, -CONH2, methylaminocarbonyl, dimethylaminocarbonyl, imidazol-2-yl, methoxy, hydroxy, bromo, carboxy, or fluoro.
The compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof wherein R¹ is hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminocarbonylalkyl, sulfonylalkyl, aminosulfonylalkyl, optionally substituted heteroaralkyl, or optionally substituted
heterocyclyl alkyl.
The compound of any one of claims 1 to 64, or a pharmaceutically acceptable salt thereof wherein R² is hydrogen, cyano, or fluoro.
A pharmaceutical composition comprising a compound of any one of claims 1 to 64 and at least one pharmaceutically acceptable excipient.
A method for treating a disease characterized by overexpression of
in a patient comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 66.
The method of claim 67, wherein the patient is in recognized need of such treatment and the disease is a cancer.
A method of treating a homologous recombinant (HR) deficient cancer in a patient comprising administering to the patient a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 66.
The method of claim 69, wherein the patient is in recognized need of such treatment.
A method for treating a cancer in a patient, wherein the cancer is characterized by a reduction or absence of BRCA gene expression, the absence of the BRAC gene, or reduced function of BRCA protein, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 64 or a pharmaceutical composition of claim 44.
The method of any one of claims 67 to 71, wherein the cancer is lymphoma, soft tissue, rhabdoid, multiple myeloma, uterus, gastric, peripheral nervous system,
rhabdomyosarcoma, bone, colorectal, mesothelioma, breast, ovarian, lung, fibroblast, central nervous system, urinary tract, upper aerodigestive, leukemia, kidney, skin, esophagus, and pancreas.