US-20260125364-A1 - HETEROAROMATIC COMPOUNDS AND THEIR USE AS DOPAMINE D1 LIGANDS

US20260125364A1US 20260125364 A1US20260125364 A1US 20260125364A1US-20260125364-A1

Abstract

The present invention provides, in part, compounds of Formula I: and pharmaceutically acceptable salts thereof; processes for the preparation of; intermediates used in the preparation of; and compositions containing such compounds or salts, and their uses for treating D1-mediated (or D1-associated) disorders including, e.g., schizophrenia (e.g., its cognitive and negative symptoms), cognitive impairment (e.g., cognitive impairment associated with schizophrenia, AD, PD, or pharmacotherapy therapy), ADHD, impulsivity, compulsive gambling, overeating, autism spectrum disorder, MCI, age-related cognitive decline, dementia, RLS, Parkinson's disease, Huntington's chorea, anxiety, depression, MDD, TRD, bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, drug abuse relapse, Tourette's syndrome, tardive dyskinesia, drowsiness, excessive daytime sleepiness, cachexia, inattention, sexual dysfunction, migraine, SLE, hyperglycemia, atherosclerosis, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, hyponatremia, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, and pain.

Inventors

Michael Aaron Brodney
Steven Victor O'Neil
Bruce Nelsen Rogers
Lei Zhang
Jennifer Elizabeth Davoren
Amy Beth Dounay
Ivan Viktorovich Efremov
DAVID LAWRENCE FIRMAN GRAY
Michael Eric Green
Jaclyn Louise Henderson
CHEWAH LEE
SCOT RICHARD MENTE

Assignees

PFIZER INC.

Dates

Publication Date: 20260507
Application Date: 20251229

Claims (2)

1 . A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: each of T 1 , T 2 , T 3 , and T 4 is independently selected from the group consisting of H, halogen, —CN, —SF 5 , —OH, —N(R a )(R b ), —C(═O)—N(R a )(R b ), —C(═O)—OR c , —C(═O)—R d , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 haloalkoxy, —S—(C 1-6 alkyl), C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 3-7 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl, wherein each of the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —S—(C 1-6 alkyl), and C 1-6 alkoxy is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, —CN, —N(R a )(R b ), C 1-4 alkoxy, C 1-4 haloalkoxy, and —S—(C 1-4 alkyl); and wherein each of the C 3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C 3-7 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl of T 1 , T 2 , and T 3 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, —CN, oxo, —N(R a )(R b ), —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —C(═O)—N(Ra)(Rb), C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, C 1-4 haloalkoxy, and —S—(C 1-4 alkyl); L 1 is selected from the group consisting of O, S, NH, N(C 1-4 alkyl), N(—C 1-2 alkyl-C 3-4 cycloalkyl), and N(C 3-6 cycloalkyl); each of R a and R b is independently selected from the group consisting of H, C 1-4 alkyl, C 3-7 cycloalkyl, and cyclopropylmethyl; or R a and R b together with the N atom to which they are attached form 4- to 7-membered heterocycloalkyl optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, —CN, oxo, —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —C(═O)OH, —C(═O)—C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—NH(C 1-4 alkyl), —C(═O)—N(C 1-4 alkyl) 2 , C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 hydroxylalkyl, C 1-4 cyanoalkyl, C 1-4 alkoxy, —S—(C 1-4 alkyl), and C 1-4 haloalkoxy; each of R c and R d is independently C 1-4 alkyl, C 3-4 cycloalkyl-C 1-2 alkyl-, or C 3-4 cycloalkyl; Q 1 is selected from the group consisting of Q 1a , Q 1b , Q 1c , Q 1d , and Q 1e : provided (a) that a ring carbon atom of the Q 1 ring is attached to the benzene ring of Formula I and (b) that when L 1 is NH, then the Q 1 ring is substituted with at least one non-H R 9 , R 10 , R 11 , R 12 , R 13 , R 9A , R 10A , R 10B , R 11A , R 12A , or R 13A ; each of X 1 and X 2 is independently O or S; each of R 1 , R 2 , R 3 , and R 4 is independently selected from the group consisting of H, halogen, —OH, —NO 2 , —CN, —SF 5 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 5 )(R 6 ), —SR 8 , and —OR 8 , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, and heterocycloalkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CN, oxo, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 3-6 cycloalkyl, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —C(═O)—OR 8 , —C(═O)H, —C(═O)R 8 , —C(═O)N(R 5 )(R 6 ), —N(R 7 )(S(═O) 2 R 8 ), —S(═O) 2 —N(R 5 )(R 6 ), —SR 8 , and —OR 8 ; or R 2 and R 4 together with the two carbon atoms to which they are attached form a fused 5- or 6-membered heteroaryl, a fused 5- or 6-membered heterocycloalkyl ring, a fused 5- or 6-membered cycloalkyl ring, or a fused benzene ring, wherein each of the fused rings is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halo, —CN, —OH, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, and C 1-4 haloalkoxy, and wherein the fused heterocycloalkyl ring or fused cycloalkyl ring is further optionally substituted with 1, 2, or 3 oxo; R 5 is H, C 1-4 alkyl, C 1-4 haloalkyl, or C 3-7 cycloalkyl; R 6 is H or selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of —OH, —CN, C 1-4 alkyl, C 3-7 cycloalkyl, C 1-4 hydroxylalkyl, —S—C 1-4 alkyl, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)—O—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , C 1-4 haloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; or R 5 and R 6 together with the N atom to which they are attached form a 4- to 10-membered heterocycloalkyl or a 5- to 10-membered heteroaryl, each optionally substituted with 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halogen, —OH, oxo, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)OH, —C(═O)—O—C 1-4 alkyl, —C(═O)—NH 2 , —C(═O)—N(C 1-4 alkyl) 2 , —CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 hydroxylalkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; R 7 is selected from the group consisting of H, C 1-4 alkyl, and C 3-7 cycloalkyl; R 8 is selected from the group consisting of C 1-6 alkyl, C 3-7 cycloalkyl, a 4- to 10-membered heterocycloalkyl, C 6-10 aryl, a 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, wherein each of the selections from the group is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, —CF 3 , —CN, —OH, oxo, —S—C 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-7 cycloalkyl, C 1-4 alkoxy, and C 1-4 haloalkoxy; each R 9 and R 12 is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl-, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —SR 8 , and —OR 8 , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxy, —N(R 5 )(R 6 ), —S—(C 1-4 alkyl), —S(═O) 2 —(C 1-4 alkyl), C 6-10 aryloxy, [(C 6-10 aryl)-C 1-4 alkyloxy-optionally substituted with 1 or 2 C 1-4 alkyl], oxo, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)O—C 1-4 alkyl, —C(═O)NH 2 , —NHC(═O)H, —NHC(═O)—(C 1-4 alkyl), C 3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; each of R 10 , R 11 and R 13 is independently selected from the group consisting of halogen, —OH, —CN, —SF 5 , —NO 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, a 4- to 10-membered heterocycloalkyl, a 5-to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl-, —N(R 5 )(R 6 ), —N(R 7 )(C(═O)R 8 ), —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —SR 8 , and —OR 8 , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl- is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxy, —N(R 5 )(R 6 ), —S—(C 1-4 alkyl), —S(═O) 2 —(C 1-4 alkyl), C 6-10 aryloxy, [(C 6-10 aryl)-C 1-4 alkyloxy-optionally substituted with 1 or 2 C 1-4 alkyl], oxo, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)O—C 1-4 alkyl, —C(═O)NH 2 , —NHC(═O)H, —NHC(═O)—(C 1-4 alkyl), C 3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; each of R 9A and R 10A is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 hydroxylalkyl, C 2-6 alkenyl, —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —SR 15 , —C(R 14 ) 2 —OH, —C(R 14 ) 2 —OS(═O) 2 H, —C(R 14 ) 2 —OP(═O)(OH) 2 , —C(R 14 ) 2 —OR 15 , —C(R 14 ) 2 —OC(═O)—R 15 , —C(R 14 ) 2 —N(R 5 )(R 6 ), each of R 10B , R 11A , R 12A , and R 13A is independently selected from the group consisting of H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 hydroxylalkyl, C 3-7 cycloalkyl, C 3-6 alkenyl, C 3-6 alkynyl, C 6-10 aryl, a 4- to 10-membered heterocycloalkyl, a 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, (5- to 10-membered heteroaryl)-C 1-4 alkyl-, —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , and —C(═O)—OR 8 , wherein each of the C 1-6 alkyl, C 3-7 cycloalkyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-7 cycloalkyl)-C 1-4 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-4 alkyl-, (C 6-10 aryl)-C 1-4 alkyl-, and (5- to 10-membered heteroaryl)-C 1-4 alkyl-, is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxy, —N(R 5 )(R 6 ), —S—(C 1-4 alkyl), —S(═O) 2 —(C 1-4 alkyl), C 6-10 aryloxy, [(C 6-10 aryl)-C 1-4 alkyloxy-optionally substituted with 1 or 2 C 1-4 alkyl], oxo, —C(═O)H, —C(═O)—C 1-4 alkyl, —C(═O)O—C 1-4 alkyl, —C(═O)NH 2 , —NHC(═O)H, —NHC(═O)—(C 1-4 alkyl), —OC(═O)—C 1-4 alkyl, C 3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; each R 14 is independently H or selected from the group consisting of C 1-10 alkyl, C 3-14 cycloalkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 6-10 aryl, 4- to 10-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-14 cycloalkyl)-C 1-10 alkyl-, (4- to 14-membered heterocycloalkyl)-C 1-10 alkyl-, (C 6-10 aryl)-C 1-10 alkyl-, (5- to 10-membered heteroaryl)-C 1-10 alkyl-, wherein each of the selections of the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxy, —N(R 5 )(R 6 ), —N(R 7 )C(═O)R 8 , —N(R 7 )C(═O)OR 8 , —N(R 7 )S(═O) 2 R 8 , —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —SR 8 , —OR 8 , —S(═O) 2 —R 8 , C 6-10 aryloxy, [(C 6-10 aryl)-C 1-4 alkyloxy-optionally substituted with 1 or 2 C 1-4 alkyl], oxo, —C(═O)H, —NHC(═O)H, C 3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; R 15 is selected from the group consisting of C 1 -2o alkyl, C 3-14 cycloalkyl, C 2-20 alkenyl, C 2 -alkynyl, C 6-10 aryl, 4- to 14-membered heterocycloalkyl, 5- to 10-membered heteroaryl, (C 3-14 cycloalkyl)-C 1-20 alkyl-, (4- to 10-membered heterocycloalkyl)-C 1-20 alkyl-, (C 6-10 aryl)-C 1-20 alkyl-, (5- to 10-membered heteroaryl)-C 1-20 alkyl-, wherein each of the selections of the group is optionally substituted with 1, 2, 3, or 4 substituents each independently selected from the group consisting of halogen, —OH, —CN, —NO 2 , C 1-4 alkyl, C 1-4 hydroxylalkyl, C 1-4 alkoxy, —N(R 5 )(R 6 ), —N(R 7 )C(═O)R 8 , —N(R 7 )C(═O)OR 8 , —N(R 7 )S(═O) 2 R 8 , —S(═O) 2 N(R 5 )(R 6 ), —C(═O)—N(R 5 )(R 6 ), —C(═O)—R 8 , —C(═O)—OR 8 , —SR 8 , —OR 8 , —S(═O) 2 —R 8 , C 6-10 aryloxy, [(C 6-10 aryl)-C 1-4 alkyloxy-optionally substituted with 1 or 2 C 1-4 alkyl], oxo, —C(═O)H, —NHC(═O)H, C 3-7 cycloalkyl, a 5- or 6-membered heteroaryl, C 1-4 haloalkyl, and C 1-4 haloalkoxy; t1 is 0, 1, or 2; t2 is 0 or 1; and t3 is 0, 1, or 2.
2 .- 61 . (canceled)

Description

FIELD OF THE INVENTION The present invention generally relates to heteroaromatic compounds, which are dopamine D1 ligands, for example dopamine D1 agonists or partial agonists. BACKGROUND OF THE INVENTION Dopamine acts upon neurons through two families of dopamine receptors, D1-like receptors (D1Rs) and D2-like receptors (D2Rs). The D1-like receptor family consists of D1 and D5 receptors which are expressed in many regions of the brain. D1 mRNA has been found, for example, in the striatum and nucleus accumbens. See e.g., Missale C, Nash S R, Robinson S W, Jaber M, Caron M G “Dopamine receptors: from structure to function”, Physiological Reviews 78:189-225 (1998). Pharmacological studies have reported that D1 and D5 receptors (D1/05), namely D1-like receptors, are linked to stimulation of adenylyl cyclase, whereas D2, D3, and D4 receptors, namely D2-like receptors, are linked to inhibition of cAMP production. Dopamine D1 receptors are implicated in numerous neuropharmacological and neurobiological functions. For example, D1 receptors are involved in different types of memory function and synaptic plasticity. See e.g., Goldman-Rakic P S et al., “Targeting the dopamine D1 receptor in schizophrenia: insights for cognitive dysfunction”, Psychopharmacology 174(1):3-16 (2004). Moreover, D1 receptors have been implicated in a variety of psychiatric, neurological, neurodevelopmental, neurodegenerative, mood, motivational, metabolic, cardiovascular, renal, ophthalmic, endocrine, and/or other disorders described herein including schizophrenia (e.g., cognitive and negative symptoms in schizophrenia), cognitive impairment associated with D2 antagonist therapy, ADHD, impulsivity, autism spectrum disorder, mild cognitive impairment (MCI), age-related cognitive decline, Alzheimer's dementia, Parkinson's disease (PD), Huntington's chorea, depression, anxiety, treatment-resistant depression (TRD), bipolar disorder, chronic apathy, anhedonia, chronic fatigue, post-traumatic stress disorder, seasonal affective disorder, social anxiety disorder, post-partum depression, serotonin syndrome, substance abuse and drug dependence, Tourette's syndrome, tardive dyskinesia, drowsiness, sexual dysfunction, migraine, systemic lupus erythematosus (SLE), hyperglycemia, dislipidemia, obesity, diabetes, sepsis, post-ischemic tubular necrosis, renal failure, resistant edema, narcolepsy, hypertension, congestive heart failure, postoperative ocular hypotonia, sleep disorders, pain, and other disorders in a mammal. See e.g., Goulet M, Madras B K “D(1) dopamine receptor agonists are more effective in alleviating advanced than mild parkinsonism in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys”, Journal of Pharmacology and Experimental Therapy 292(2):714-24 (2000); Surmeier D J et al., “The role of dopamine in modulating the structure and function of striatal circuits”, Prog. Brain Res. 183:149-67 (2010). New or improved agents that modulate (such as agonize or partially agonize) D1 are needed for developing new and more effective pharmaceuticals to treat diseases or conditions associated with dysregulated activation of D1, such as those described herein. SUMMARY OF THE INVENTION The present invention provides, in part, a compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein: each of T1, T2, T3, and T4 is independently selected from the group consisting of H, halogen, —CN, —SF5, —OH, —N(Ra)(Rb), —C(═O)—N(Ra)(Rb), —C(═O)—ORc, —C(═O)—Rd, C1-6 alkyl, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 haloalkoxy, —S—(C1-6 alkyl), C3-7 cycloalkyl, 4-to 7-membered heterocycloalkyl, C3-7 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl, wherein each of the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, —S—(C1-6 alkyl), and C1-6 alkoxy is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, —CN, —N(Ra)(Rb), C1-4 alkoxy, C1-4 haloalkoxy, and —S—(C1-4 alkyl); and wherein each of the C3-7 cycloalkyl, 4- to 7-membered heterocycloalkyl, C3-7 cycloalkoxy, 5- or 6-membered heteroaryl, cyclopropylmethyl, and cyclobutylmethyl of T1, T2, and T3 is optionally substituted with one or more substituents each independently selected from the group consisting of halogen, —OH, —CN, oxo, —N(Ra)(Rb), —C(═O)OH, —C(═O)—C1-4 alkyl, —C(═O)—O—C1-4 alkyl, —C(═O)—N(Ra)(Rb), C1-4 alkyl, C1-4 haloalkyl, C1-4 hydroxylalkyl, C1-4 cyanoalkyl, C1-4 alkoxy, C1-4 haloalkoxy, and —S—(C1-4 alkyl);L1 is selected from the group consisting of O, S, NH, N(C1-4 alkyl), N(—C1-2 alkyl-C3-4 cycloalkyl), and N(C3-6 cycloalkyl);each of Ra and Rb is independently selected from the group consisting of H, C1-4 alkyl, C3-7 cycloalkyl (e.g., cyclopropyl, cyclobutyl, bicyclo[1.1.1]pentan-1-yl, or bicyclo[1.1.1]pentan-2-yl), and cyclopropylmethyl;or Ra and Rb together with the N atom to which they are attached form 4- to 7-membered heterocycloalkyl (e.g., azetidinyl