While I can't speak to more recent reasons why this are has not seen development, I can attest that it is not because this region was impenetrable or inhospitable to human settlement.

We know that at the time of the Spanish arrival in the early 1500s, the entire region from what is now Colombia around the Gulf of Darien and through all of Eastern Panama was inhabited by Indigenous peoples. Anthropologists have classified most of these groups as petty chiefdoms. The groups that inhabited the Darien Gap were known to the Spanish as the 'Cueva' or 'the people who speak Cueva'. The two most detailed accounts are by Antonio de Herrera (he was actually present and participated in the conquest of this region) and Bartolome de las Casas. The densest area of Cueva settlement appeared to be the region between the Gulf of Darien on the Atlantic side and the Gulf of San Miguel on the Pacific side. Spaniards provided a very detailed list of the largest groups in the region. Some of these included Careta, Ponca, Darien (yes the name is in fact from an Indigenous chiefdom), Chochama, Chape, Tumaco, etc.

Spanish conquest during this time was particularly brutal. Las Casas singles out Panama as one of the most violent and destructive conquests of the period. Although the Spanish did use some alliances to further their efforts, frequently they turned against indigenous allies enslaving them and transporting them back to Santa Maria la Antigua del Darien. This was their first settlement in the region located on the western shore of the Gulf of Darien, the site of their first conquest, the chiefdom of Darien. Over the course of about 5 years, the Spanish systematically raided, enslaved, and relocated the Cueva.

The devastation and decimation was so total that even conquistadors began to note the evident depopulation of the region. Those efforts, and the genocide of possibly hundreds of thousands of Cueva eventually led the Spanish to set their sights on groups farther to the west. They had already gone on raids to the Azuero Peninsula (west of modern day Panama City) and knew that there were still numerous chiefdoms in that region. The desire to target those regions coupled with some political infighting in Santa Maria led the Spanish governor, Pedrarias Davila, to move the seat of government to the west, where he founded Panama City.

When this happened, 1519, some Spaniards still remained in Santa Maria and at a town named Acla farther up the coast to the west. However, with few indigenous people remaining to serve as laborers these communities struggled on with very few residents. By the mid-1520s, the Spanish considered the eastern isthmus devoid of indigenous inhabitants. Now this was not exactly the case, there were likely some isolated hamlets that had evaded the conquests of 1514-1519, but these were few and likely had few inhabitants.

But this is not the end of the story, beginning almost immediately after the indigenous population was decimated, Spanish Panama became one of the largest importers of enslaved Africans. We know that by 1570 over 3/4 of the population was African and most were enslaved. They filled every single labor niche in the colony.

It should also be noted that Spanish Panama was two cities: Nombre de Dios on the Atlantic and Panama City on the Pacific. There was a road that linked the two of them. That was it. There were two indigenous communities of note that remained in the sixteenth century, one located along the Rio Chepo just east of Panama City and another located to the west of Panama City. What we call the Darien Gap had no Spanish settlement after about 1550.

But that does not mean that Spanish colonialism didn't lead to settlement there. All those Africans that were brought in bondage, many chose to escape enslavement. The eastern isthmus represented an ideal location for establishing communities outside of Spanish control.

From the 1530s, if not earlier through the 1580s, the eastern isthmus was home to multiple, sizable maroon communities. Maroon comes from the Spanish word cimarron (which comes from a Taino word) and means runaway. It could be applied to livestock or people, usually Africans.

Throughout this period, maroons lived in the region and raided Spaniards for supplies (particularly manufactured goods) and to free other enslaved Africans. In general, the Spanish used periodic campaigns to try and recapture/kill/disperse the maroons that had taken to the area.

In the early 1550s, the maroons lived under a 'king' named Bayano. At least 4 campaigns were sent out against him and his people. The maroons maintained at least two major settlements. There was at least one indigenous community that appears to have had close associations with the maroons, quite possibly one of the last Cueva communities.

Around 1555, Bayano was captured by a Spanish captain named Pedro de Ursua. However, his captivity came through treachery. Ursua had been unable to defeat Bayano and his people, so he offered a truce to negotiate a peace agreement. He offered Bayano and his people freedom and their own self-governing community in return for their help in preventing future runaways. But before that could be agreed to, Ursua drugged Bayano and his captains at a feast, capturing Bayano and slaying many of his people.

That did not end the maroon settlement of the Darien Gap. Many maroons escaped. Between the 1550s and 1570s, at least four major settlements likely existed with between several score and several hundred residents. Spaniards continued to use periodic raids, but these tended to be ineffective.

Things changed in the 1570s when English raiders began to forge alliances with the maroons of the eastern isthmus. In 1573 and again in 1576/7, English raiders used alliances with maroons to raid deep into the isthmus. In 1573, maroons aided Francis Drake in attacking the road between Nombre de Dios and Panama capturing a large quantity of gold and silver. In 1576, John Oxenham, a shipmate of Drake's, returned and used maroon alliances to cross into the Gulf of San Miguel, build small craft, capture a Spanish trading ship, and then raid the Pearl Islands (where Spaniards used enslaved Africans as pearl divers).

These raids sparked a prolonged war between the Spanish and the maroons. In 1577, the Spanish succeeded in trapping Oxenham and his men on the isthmus. The Spanish then undertook a scorched earth campaign to root out the English and punish the maroons. However, the maroons dispersed and countered the Spanish efforts with guerrilla tactics. After several years, some maroons approached the Spanish to see if they would agree to a peace (very similar to that originally proposed to Bayano).

In 1579, a group of maroons from the Bay of Portobelo (just west of Nombre de Dios) secured such a peace. In return for their freedom they would help the Spanish against other maroons and foreign invaders. They moved their community to just outside of Nombre de Dios, it received a Spanish charter as Santiago del Principe.

The maroons of the eastern isthmus, often called the Bayano for the earlier maroon king, negotiated a peace, but it broke down. After two more years of fighting, the maroons again reached out about a peace and the Spanish exhausted by the costly campaigns agreed to the peace. The maroons of the Bayano were settled in a town named Santa Cruz la Real near Panama City, now probably under the Panama Canal.

These represent the first two free-black communities in the Americas.

While the peace removed the maroons from the eastern isthmus, it did not end enslaved flight. Africans continued to flee to the region. However, the newly freed maroons did follow through on their promise to track down runaways.

Additionally, indigenous groups from south of the Darien began a period of migration north and west. These groups had never been conquered (Spanish conquests in Panama and Colombia had largely avoided the region south of the Gulf of Darien, down the Atrato River). In part, this was because the groups here were fiercely territorial and prevented any Spanish penetration. By the 1590s/1600s, a group that the Spanish initially called 'indios buque buque' began to migrate north into the region between the Gulf of Darien and the Gulf of San Miguel. Although the Spanish, aided by former maroons, tried to prevent this movement, they were unable to stop it. In all likelihood the indios buque buque were the group now known as the Guna or Kuna people that continue to inhabit the eastern isthmus.

The Spanish occasionally tried to reassert some control around the Gulf of San Miguel. By the late 17th c. there were some mining and logging interests there. Around the same time, the Spanish began to adopt a 'peaceful' conquest strategy through missionaries that nominally brought these indigenous inhabitants into the Spanish orbit. Yet even by 1700, the indigenous inhabitants remained largely politically independent. Some even went so far as to help the Scots during their failed attempt to set up a colony in the region (New Caledonia).

That brings things to 1700, and shows that this region was not a no-mans-land but was instead a region inhabited by various groups over a long period of time. In the Spanish colonial period, it is a perfect example of a place that the Spanish claimed but never really managed to control. Often, Spanish political discourse covered up such failures by claiming that such regions were 'despoblado' uninhabited when in reality it was more that they were devoid of Spanish settlements/interests.

So there you have it from the pre-Colombian through the early 18th c. the region was anything but uninhabited.